diff --git a/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.spec.ts b/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.spec.ts
index 9d284db11a2a..3d173e584117 100644
--- a/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.spec.ts
+++ b/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.spec.ts
@@ -8,6 +8,7 @@ import { flexibleChecksumsMiddleware } from "./flexibleChecksumsMiddleware";
 import { getChecksumAlgorithmForRequest } from "./getChecksumAlgorithmForRequest";
 import { getChecksumLocationName } from "./getChecksumLocationName";
 import { hasHeader } from "./hasHeader";
+import { hasHeaderWithPrefix } from "./hasHeaderWithPrefix";
 import { isStreaming } from "./isStreaming";
 import { selectChecksumAlgorithmFunction } from "./selectChecksumAlgorithmFunction";
 import { stringHasher } from "./stringHasher";
@@ -16,6 +17,7 @@ vi.mock("@smithy/protocol-http");
 vi.mock("./getChecksumAlgorithmForRequest");
 vi.mock("./getChecksumLocationName");
 vi.mock("./hasHeader");
+vi.mock("./hasHeaderWithPrefix");
 vi.mock("./isStreaming");
 vi.mock("./selectChecksumAlgorithmFunction");
 vi.mock("./stringHasher");
@@ -44,6 +46,7 @@ describe(flexibleChecksumsMiddleware.name, () => {
     vi.mocked(getChecksumAlgorithmForRequest).mockReturnValue(ChecksumAlgorithm.MD5);
     vi.mocked(getChecksumLocationName).mockReturnValue(mockChecksumLocationName);
     vi.mocked(hasHeader).mockReturnValue(true);
+    vi.mocked(hasHeaderWithPrefix).mockReturnValue(false);
     vi.mocked(isStreaming).mockReturnValue(false);
     vi.mocked(selectChecksumAlgorithmFunction).mockReturnValue(mockChecksumAlgorithmFunction);
   });
@@ -63,31 +66,28 @@ describe(flexibleChecksumsMiddleware.name, () => {
     });
 
     describe("request checksum", () => {
-      afterEach(() => {
-        expect(getChecksumAlgorithmForRequest).toHaveBeenCalledTimes(1);
-      });
-
       it("if checksumAlgorithm is not defined", async () => {
         vi.mocked(getChecksumAlgorithmForRequest).mockReturnValue(undefined);
         const handler = flexibleChecksumsMiddleware(mockConfig, mockMiddlewareConfig)(mockNext, {});
         await handler(mockArgs);
+        expect(hasHeaderWithPrefix).toHaveBeenCalledTimes(1);
         expect(getChecksumLocationName).not.toHaveBeenCalled();
         expect(mockNext).toHaveBeenCalledWith(mockArgs);
         expect(selectChecksumAlgorithmFunction).not.toHaveBeenCalled();
+        expect(getChecksumAlgorithmForRequest).toHaveBeenCalledTimes(1);
       });
 
       it("if header is already present", async () => {
         const handler = flexibleChecksumsMiddleware(mockConfig, mockMiddlewareConfig)(mockNext, {});
-        const mockHeadersWithChecksumHeader = { ...mockHeaders, [mockChecksumLocationName]: "mockHeaderValue" };
-        const mockArgsWithChecksumHeader = {
-          ...mockArgs,
-          request: { ...mockRequest, headers: mockHeadersWithChecksumHeader },
-        };
-        await handler(mockArgsWithChecksumHeader);
-        expect(getChecksumLocationName).toHaveBeenCalledWith(ChecksumAlgorithm.MD5);
-        expect(selectChecksumAlgorithmFunction).toHaveBeenCalledWith(ChecksumAlgorithm.MD5, mockConfig);
-        expect(mockNext).toHaveBeenCalledWith(mockArgsWithChecksumHeader);
-        expect(hasHeader).toHaveBeenCalledWith(mockChecksumLocationName, mockHeadersWithChecksumHeader);
+        vi.mocked(hasHeaderWithPrefix).mockReturnValue(true);
+
+        await handler(mockArgs);
+
+        expect(hasHeaderWithPrefix).toHaveBeenCalledTimes(1);
+        expect(getChecksumLocationName).not.toHaveBeenCalled();
+        expect(selectChecksumAlgorithmFunction).not.toHaveBeenCalled();
+        expect(hasHeader).not.toHaveBeenCalled();
+        expect(mockNext).toHaveBeenCalledWith(mockArgs);
       });
     });
   });
diff --git a/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.ts b/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.ts
index 7a19714e8755..470a2fcc08e6 100644
--- a/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.ts
+++ b/packages/middleware-flexible-checksums/src/flexibleChecksumsMiddleware.ts
@@ -15,6 +15,7 @@ import { ChecksumAlgorithm } from "./constants";
 import { getChecksumAlgorithmForRequest } from "./getChecksumAlgorithmForRequest";
 import { getChecksumLocationName } from "./getChecksumLocationName";
 import { hasHeader } from "./hasHeader";
+import { hasHeaderWithPrefix } from "./hasHeaderWithPrefix";
 import { isStreaming } from "./isStreaming";
 import { selectChecksumAlgorithmFunction } from "./selectChecksumAlgorithmFunction";
 import { stringHasher } from "./stringHasher";
@@ -64,6 +65,10 @@ export const flexibleChecksumsMiddleware =
       return next(args);
     }
 
+    if (hasHeaderWithPrefix("x-amz-checksum-", args.request.headers)) {
+      return next(args);
+    }
+
     const { request, input } = args;
     const { body: requestBody, headers } = request;
     const { base64Encoder, streamHasher } = config;
diff --git a/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.spec.ts b/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.spec.ts
new file mode 100644
index 000000000000..c69652d7935e
--- /dev/null
+++ b/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.spec.ts
@@ -0,0 +1,29 @@
+import { HeaderBag } from "@smithy/types";
+import { describe, expect, test as it } from "vitest";
+
+import { hasHeaderWithPrefix } from "./hasHeaderWithPrefix";
+
+describe(hasHeaderWithPrefix.name, () => {
+  const mockHeaders: HeaderBag = {
+    "header-prefix-lowercase-1": "header-value-1",
+    "HEADER-PREFIX-UPPERCASE-2": "header-value-2",
+  };
+
+  describe("contains header prefix", () => {
+    it("when headerPrefix is exact", () => {
+      expect(hasHeaderWithPrefix("header-prefix-lowercase-", mockHeaders)).toBe(true);
+    });
+
+    it("when headerPrefix is in different case", () => {
+      expect(hasHeaderWithPrefix("HEADER-PREFIX-LOWERCASE-", mockHeaders)).toBe(true);
+    });
+
+    it("when headerPrefix in headers is in different case", () => {
+      expect(hasHeaderWithPrefix("header-prefix-uppercase-", mockHeaders)).toBe(true);
+    });
+  });
+
+  it("doesn't contain header with headerPrefix", () => {
+    expect(hasHeaderWithPrefix("header-prefix-3", mockHeaders)).toBe(false);
+  });
+});
diff --git a/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.ts b/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.ts
new file mode 100644
index 000000000000..9ef8401fecf7
--- /dev/null
+++ b/packages/middleware-flexible-checksums/src/hasHeaderWithPrefix.ts
@@ -0,0 +1,15 @@
+import { HeaderBag } from "@smithy/types";
+
+/**
+ * Returns true if header with headerPrefix is present in headers.
+ * Comparisons are case-insensitive.
+ */
+export const hasHeaderWithPrefix = (headerPrefix: string, headers: HeaderBag): boolean => {
+  const soughtHeaderPrefix = headerPrefix.toLowerCase();
+  for (const headerName of Object.keys(headers)) {
+    if (headerName.toLowerCase().startsWith(soughtHeaderPrefix)) {
+      return true;
+    }
+  }
+  return false;
+};