diff --git a/packages/react/src/components/ComboBox/ComboBox-test.js b/packages/react/src/components/ComboBox/ComboBox-test.js
index 2252549a8cb8..7bfe47f8f4b2 100644
--- a/packages/react/src/components/ComboBox/ComboBox-test.js
+++ b/packages/react/src/components/ComboBox/ComboBox-test.js
@@ -7,6 +7,8 @@
 
 import React from 'react';
 import { mount } from 'enzyme';
+import { render, screen, within } from '@testing-library/react';
+import userEvent from '@testing-library/user-event';
 import {
   findListBoxNode,
   findMenuNode,
@@ -201,5 +203,49 @@ describe('ComboBox', () => {
       const wrapper = mount(<ComboBox {...mockProps} />);
       expect(wrapper.find('input').instance().value).toBe('');
     });
+
+    it('should only render one listbox at a time when multiple comboboxes are present', () => {
+      render(
+        <>
+          <div data-testid="combobox-1">
+            <ComboBox {...mockProps} id="combobox-1" />
+          </div>
+          <div data-testid="combobox-2">
+            <ComboBox {...mockProps} id="combobox-2" />
+          </div>
+        </>
+      );
+      const firstCombobox = screen.getByTestId('combobox-1');
+      const secondCombobox = screen.getByTestId('combobox-2');
+
+      const firstComboboxChevron = within(firstCombobox).getByRole('button');
+      const secondComboboxChevron = within(secondCombobox).getByRole('button');
+
+      function firstListBox() {
+        return within(firstCombobox).getByRole('listbox');
+      }
+
+      function secondListBox() {
+        return within(secondCombobox).getByRole('listbox');
+      }
+
+      expect(firstListBox()).toBeEmptyDOMElement();
+      expect(secondListBox()).toBeEmptyDOMElement();
+
+      userEvent.click(firstComboboxChevron);
+
+      expect(firstListBox()).not.toBeEmptyDOMElement();
+      expect(secondListBox()).toBeEmptyDOMElement();
+
+      userEvent.click(secondComboboxChevron);
+
+      expect(firstListBox()).toBeEmptyDOMElement();
+      expect(secondListBox()).not.toBeEmptyDOMElement();
+
+      userEvent.click(secondComboboxChevron);
+
+      expect(firstListBox()).toBeEmptyDOMElement();
+      expect(secondListBox()).toBeEmptyDOMElement();
+    });
   });
 });
diff --git a/packages/react/src/components/ComboBox/ComboBox.js b/packages/react/src/components/ComboBox/ComboBox.js
index af8d885bcc9b..4db995c2ca3d 100644
--- a/packages/react/src/components/ComboBox/ComboBox.js
+++ b/packages/react/src/components/ComboBox/ComboBox.js
@@ -252,11 +252,13 @@ const ComboBox = React.forwardRef((props, ref) => {
           // https://github.com/downshift-js/downshift/blob/v5.2.1/src/downshift.js#L1051-L1065
           //
           // As a result, it will reset the state of the component and so we
-          // stop the event from propagating to prevent this. This allows the
-          // toggleMenu behavior for the toggleButton to correctly open and
+          // stop the event from propagating to prevent this if the menu is already open.
+          // This allows the toggleMenu behavior for the toggleButton to correctly open and
           // close the menu.
           onMouseUp(event) {
-            event.stopPropagation();
+            if (isOpen) {
+              event.stopPropagation();
+            }
           },
         });
         const inputProps = getInputProps({