diff --git a/CHANGELOG.md b/CHANGELOG.md
index e76da292e3f4..c4d96da84e49 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -19,6 +19,10 @@ and this project adheres to [Semantic Versioning](https://semver.org/spec/v2.0.0
 - Add `caption-side` utilities ([#10470](https://github.com/tailwindlabs/tailwindcss/pull/10470))
 - Add `justify-normal` and `justify-stretch` utilities ([#10560](https://github.com/tailwindlabs/tailwindcss/pull/10560))
 
+### Fixed
+
+- Disallow multiple selectors in arbitrary variants ([#10655](https://github.com/tailwindlabs/tailwindcss/pull/10655))
+
 ### Changed
 
 - [Oxide] Disable color opacity plugins by default in the `oxide` engine ([#10618](https://github.com/tailwindlabs/tailwindcss/pull/10618))
diff --git a/src/lib/generateRules.js b/src/lib/generateRules.js
index f7096e556602..0306893ad3ef 100644
--- a/src/lib/generateRules.js
+++ b/src/lib/generateRules.js
@@ -205,17 +205,26 @@ function applyVariant(variant, matches, context) {
 
   // Register arbitrary variants
   if (isArbitraryValue(variant) && !context.variantMap.has(variant)) {
+    let sort = context.offsets.recordVariant(variant)
+
     let selector = normalize(variant.slice(1, -1))
+    let selectors = splitAtTopLevelOnly(selector, ',')
 
-    if (!isValidVariantFormatString(selector)) {
+    // We do not support multiple selectors for arbitrary variants
+    if (selectors.length > 1) {
       return []
     }
 
-    let fn = parseVariant(selector)
+    if (!selectors.every(isValidVariantFormatString)) {
+      return []
+    }
 
-    let sort = context.offsets.recordVariant(variant)
+    let records = selectors.map((sel, idx) => [
+      context.offsets.applyParallelOffset(sort, idx),
+      parseVariant(sel.trim()),
+    ])
 
-    context.variantMap.set(variant, [[sort, fn]])
+    context.variantMap.set(variant, records)
   }
 
   if (context.variantMap.has(variant)) {
diff --git a/src/util/splitAtTopLevelOnly.js b/src/util/splitAtTopLevelOnly.js
index 63fd767403ce..a749c7932ed9 100644
--- a/src/util/splitAtTopLevelOnly.js
+++ b/src/util/splitAtTopLevelOnly.js
@@ -17,17 +17,24 @@ export function splitAtTopLevelOnly(input, separator) {
   let stack = []
   let parts = []
   let lastPos = 0
+  let isEscaped = false
 
   for (let idx = 0; idx < input.length; idx++) {
     let char = input[idx]
 
-    if (stack.length === 0 && char === separator[0]) {
+    if (stack.length === 0 && char === separator[0] && !isEscaped) {
       if (separator.length === 1 || input.slice(idx, idx + separator.length) === separator) {
         parts.push(input.slice(lastPos, idx))
         lastPos = idx + separator.length
       }
     }
 
+    if (isEscaped) {
+      isEscaped = false
+    } else if (char === '\\') {
+      isEscaped = true
+    }
+
     if (char === '(' || char === '[' || char === '{') {
       stack.push(char)
     } else if (
diff --git a/tests/arbitrary-variants.test.js b/tests/arbitrary-variants.test.js
index 46da5cdf2027..b210bdc77ecb 100644
--- a/tests/arbitrary-variants.test.js
+++ b/tests/arbitrary-variants.test.js
@@ -1116,6 +1116,53 @@ crosscheck(({ stable, oxide }) => {
     })
   })
 
+  it('it should discard arbitrary variants with multiple selectors', () => {
+    let config = {
+      content: [
+        {
+          raw: html`
+            <div class="p-1"></div>
+            <div class="[div]:p-1"></div>
+            <div class="[div_&]:p-1"></div>
+            <div class="[div,span]:p-1"></div>
+            <div class="[div_&,span]:p-1"></div>
+            <div class="[div,span_&]:p-1"></div>
+            <div class="[div_&,span_&]:p-1"></div>
+            <div class="hover:[div]:p-1"></div>
+            <div class="hover:[div_&]:p-1"></div>
+            <div class="hover:[div,span]:p-1"></div>
+            <div class="hover:[div_&,span]:p-1"></div>
+            <div class="hover:[div,span_&]:p-1"></div>
+            <div class="hover:[div_&,span_&]:p-1"></div>
+            <div class="hover:[:is(span,div)_&]:p-1"></div>
+          `,
+        },
+        {
+          // escaped commas are a-ok
+          // This is separate because prettier complains about `\,` in the template string
+          raw: '<div class="hover:[.span\\,div_&]:p-1"></div>',
+        },
+      ],
+      corePlugins: { preflight: false },
+    }
+
+    let input = css`
+      @tailwind utilities;
+    `
+
+    return run(input, config).then((result) => {
+      expect(result.css).toMatchFormattedCss(css`
+        .p-1,
+        .span\,div .hover\:\[\.span\\\,div_\&\]\:p-1:hover,
+        :is(span, div) .hover\:\[\:is\(span\,div\)_\&\]\:p-1:hover,
+        div .\[div_\&\]\:p-1,
+        div .hover\:\[div_\&\]\:p-1:hover {
+          padding: 0.25rem;
+        }
+      `)
+    })
+  })
+
   it('should sort multiple variant fns with normal variants between them', () => {
     /** @type {string[]} */
     let lines = []