diff --git a/lib/core/request.js b/lib/core/request.js
index 8e2072a46c7..d79526c57ef 100644
--- a/lib/core/request.js
+++ b/lib/core/request.js
@@ -47,6 +47,8 @@ const kHandler = Symbol('handler')
 const kController = Symbol('controller')
 const kResume = Symbol('resume')
 
+let isUndiciFormData
+
 class RequestController {
   #paused = false
   #reason = null
@@ -206,7 +208,13 @@ class Request {
       this.body = body.byteLength ? Buffer.from(body) : null
     } else if (typeof body === 'string') {
       this.body = body.length ? Buffer.from(body) : null
-    } else if (isFormDataLike(body) || isIterable(body) || isBlobLike(body)) {
+    } else if (isFormDataLike(body)) {
+      isUndiciFormData ??= require('../web/webidl').webidl.is.FormData
+      if (!isUndiciFormData(body)) {
+        throw new InvalidArgumentError('FormData body must be an instance of undici\'s FormData class. FormData objects from other realms (e.g. Node.js\' global FormData) are not supported.')
+      }
+      this.body = body
+    } else if (isIterable(body) || isBlobLike(body)) {
       this.body = body
     } else {
       throw new InvalidArgumentError('body must be a string, a Buffer, a Readable stream, an iterable, or an async iterable')
diff --git a/test/issue-5520.js b/test/issue-5520.js
new file mode 100644
index 00000000000..b343fac7f3f
--- /dev/null
+++ b/test/issue-5520.js
@@ -0,0 +1,54 @@
+'use strict'
+
+const { test } = require('node:test')
+const { createServer } = require('node:http')
+const { createServer: createH2Server } = require('node:http2')
+const { once } = require('node:events')
+const { request, H2CClient, errors } = require('..')
+
+// https://github.com/nodejs/undici/issues/5520
+
+test('request() rejects a cross-realm (Node builtin) FormData body', { timeout: 60000 }, async (t) => {
+  const server = createServer((req, res) => {
+    req.on('data', () => {})
+    req.on('end', () => res.end('{}'))
+  })
+  t.after(() => {
+    server.closeAllConnections?.()
+    server.close()
+  })
+
+  server.listen(0)
+  await once(server, 'listening')
+
+  const form = new globalThis.FormData()
+  form.append('field', 'value')
+  form.append('file', new Blob(['file contents'], { type: 'text/plain' }), 'hello.txt')
+
+  await t.assert.rejects(
+    request(`http://localhost:${server.address().port}/`, { method: 'POST', body: form }),
+    errors.InvalidArgumentError
+  )
+})
+
+test('HTTP/2 client rejects a cross-realm (Node builtin) FormData body', { timeout: 60000 }, async (t) => {
+  const server = createH2Server((req, res) => {
+    req.on('data', () => {})
+    req.on('end', () => res.end('{}'))
+  })
+  t.after(() => server.close())
+
+  server.listen(0)
+  await once(server, 'listening')
+
+  const client = new H2CClient(`http://localhost:${server.address().port}`)
+  t.after(() => client.close())
+
+  const form = new globalThis.FormData()
+  form.append('field', 'value')
+
+  await t.assert.rejects(
+    client.request({ path: '/', method: 'POST', body: form }),
+    errors.InvalidArgumentError
+  )
+})