diff --git a/lib/handler/cache-handler.js b/lib/handler/cache-handler.js
index e02ff9c9d72..b8a882381c2 100644
--- a/lib/handler/cache-handler.js
+++ b/lib/handler/cache-handler.js
@@ -4,7 +4,8 @@ const util = require('../core/util')
 const {
   parseCacheControlHeader,
   parseVaryHeader,
-  isEtagUsable
+  isEtagUsable,
+  makeHeaderNamesLowercase
 } = require('../util/cache')
 const { parseHttpDate } = require('../util/date.js')
 
@@ -111,11 +112,13 @@ class CacheHandler {
       return downstreamOnHeaders()
     }
 
-    const cacheControlHeader = resHeaders['cache-control']
-    const heuristicallyCacheable = resHeaders['last-modified'] && HEURISTICALLY_CACHEABLE_STATUS_CODES.includes(statusCode)
+    const resHeadersLowercase = makeHeaderNamesLowercase(resHeaders)
+
+    const cacheControlHeader = resHeadersLowercase['cache-control']
+    const heuristicallyCacheable = resHeadersLowercase['last-modified'] && HEURISTICALLY_CACHEABLE_STATUS_CODES.includes(statusCode)
     if (
       !cacheControlHeader &&
-      !resHeaders['expires'] &&
+      !resHeadersLowercase.expires &&
       !heuristicallyCacheable &&
       !this.#cacheByDefault
     ) {
@@ -125,23 +128,23 @@ class CacheHandler {
     }
 
     const cacheControlDirectives = cacheControlHeader ? parseCacheControlHeader(cacheControlHeader) : {}
-    if (!canCacheResponse(this.#cacheType, statusCode, resHeaders, cacheControlDirectives)) {
+    if (!canCacheResponse(this.#cacheType, statusCode, resHeadersLowercase, cacheControlDirectives)) {
       return downstreamOnHeaders()
     }
 
     const now = Date.now()
-    const resAge = resHeaders.age ? getAge(resHeaders.age) : undefined
+    const resAge = resHeadersLowercase.age ? getAge(resHeadersLowercase.age) : undefined
     if (resAge && resAge >= MAX_RESPONSE_AGE) {
       // Response considered stale
       return downstreamOnHeaders()
     }
 
-    const resDate = typeof resHeaders.date === 'string'
-      ? parseHttpDate(resHeaders.date)
+    const resDate = typeof resHeadersLowercase.date === 'string'
+      ? parseHttpDate(resHeadersLowercase.date)
       : undefined
 
     const staleAt =
-      determineStaleAt(this.#cacheType, now, resAge, resHeaders, resDate, cacheControlDirectives) ??
+      determineStaleAt(this.#cacheType, now, resAge, resHeadersLowercase, resDate, cacheControlDirectives) ??
       this.#cacheByDefault
     if (staleAt === undefined || (resAge && resAge > staleAt)) {
       return downstreamOnHeaders()
@@ -155,8 +158,9 @@ class CacheHandler {
     }
 
     let varyDirectives
-    if (this.#cacheKey.headers && resHeaders.vary) {
-      varyDirectives = parseVaryHeader(resHeaders.vary, this.#cacheKey.headers)
+    if (this.#cacheKey.headers && resHeadersLowercase.vary) {
+      varyDirectives = parseVaryHeader(resHeadersLowercase.vary, this.#cacheKey.headers)
+
       if (!varyDirectives) {
         // Parse error
         return downstreamOnHeaders()
@@ -164,7 +168,7 @@ class CacheHandler {
     }
 
     const deleteAt = determineDeleteAt(baseTime, cacheControlDirectives, absoluteStaleAt)
-    const strippedHeaders = stripNecessaryHeaders(resHeaders, cacheControlDirectives)
+    const strippedHeaders = stripNecessaryHeaders(resHeadersLowercase, cacheControlDirectives)
 
     /**
      * @type {import('../../types/cache-interceptor.d.ts').default.CacheValue}
@@ -180,8 +184,8 @@ class CacheHandler {
       deleteAt
     }
 
-    if (typeof resHeaders.etag === 'string' && isEtagUsable(resHeaders.etag)) {
-      value.etag = resHeaders.etag
+    if (typeof resHeadersLowercase.etag === 'string' && isEtagUsable(resHeadersLowercase.etag)) {
+      value.etag = resHeadersLowercase.etag
     }
 
     this.#writeStream = this.#store.createWriteStream(this.#cacheKey, value)
diff --git a/lib/util/cache.js b/lib/util/cache.js
index 35c53512b2a..175f9cfe49a 100644
--- a/lib/util/cache.js
+++ b/lib/util/cache.js
@@ -38,7 +38,7 @@ function makeCacheKey (opts) {
     origin: opts.origin.toString(),
     method: opts.method,
     path: opts.path,
-    headers
+    headers: makeHeaderNamesLowercase(headers)
   }
 }
 
@@ -347,6 +347,20 @@ function assertCacheMethods (methods, name = 'CacheMethods') {
   }
 }
 
+/**
+ * @param {import('../../types/header.d.ts').IncomingHttpHeaders} headers
+ * @returns {import('../../types/header.d.ts').IncomingHttpHeaders}
+ */
+function makeHeaderNamesLowercase (headers) {
+  const lowercased = {}
+
+  for (const header of Object.keys(headers)) {
+    lowercased[header.toLowerCase()] = headers[header]
+  }
+
+  return lowercased
+}
+
 module.exports = {
   makeCacheKey,
   assertCacheKey,
@@ -355,5 +369,6 @@ module.exports = {
   parseVaryHeader,
   isEtagUsable,
   assertCacheMethods,
-  assertCacheStore
+  assertCacheStore,
+  makeHeaderNamesLowercase
 }
diff --git a/test/interceptors/cache.js b/test/interceptors/cache.js
index dc120c60b7b..9a77fa1600f 100644
--- a/test/interceptors/cache.js
+++ b/test/interceptors/cache.js
@@ -128,6 +128,51 @@ describe('Cache Interceptor', () => {
     }
   })
 
+  test('vary directives are case-insensitive', async () => {
+    let requestsToOrigin = 0
+    const server = createServer((_, res) => {
+      requestsToOrigin++
+
+      res.setHeader('date', 0)
+      res.setHeader('cache-control', 'max-age=5000')
+      res.setHeader('vary', 'FoO, bar, bAZ')
+
+      res.end('asd')
+    }).listen(0)
+
+    const client = new Client(`http://localhost:${server.address().port}`)
+      .compose(interceptors.cache())
+
+    after(async () => {
+      server.close()
+      await client.close()
+    })
+
+    await once(server, 'listening')
+
+    strictEqual(requestsToOrigin, 0)
+
+    /**
+     * @type {import('../../types/dispatcher').default.RequestOptions}
+     */
+    const request = {
+      origin: 'localhost',
+      method: 'GET',
+      path: '/',
+      headers: {
+        Foo: '1',
+        BAr: 'abc',
+        BAZ: '789'
+      }
+    }
+
+    await client.request(request)
+    equal(requestsToOrigin, 1)
+
+    await client.request(request)
+    equal(requestsToOrigin, 1)
+  })
+
   test('stale responses are revalidated before deleteAt (if-modified-since)', async () => {
     const clock = FakeTimers.install({
       shouldClearNativeTimers: true