diff --git a/core-server/src/main/java/org/glassfish/jersey/server/model/RuntimeResourceModelValidator.java b/core-server/src/main/java/org/glassfish/jersey/server/model/RuntimeResourceModelValidator.java
index fc935b09e3..2001233a94 100644
--- a/core-server/src/main/java/org/glassfish/jersey/server/model/RuntimeResourceModelValidator.java
+++ b/core-server/src/main/java/org/glassfish/jersey/server/model/RuntimeResourceModelValidator.java
@@ -1,5 +1,5 @@
 /*
- * Copyright (c) 2013, 2018 Oracle and/or its affiliates. All rights reserved.
+ * Copyright (c) 2013, 2021 Oracle and/or its affiliates. All rights reserved.
  *
  * This program and the accompanying materials are made available under the
  * terms of the Eclipse Public License v. 2.0, which is available at
@@ -103,9 +103,14 @@ private void checkIntersectingMediaTypes(
         }
 
         if (consumesFails && producesFails) {
-            // fatal
-            Errors.fatal(runtimeResource, LocalizationMessages.AMBIGUOUS_FATAL_RMS(httpMethod, m1.getInvocable()
-                    .getHandlingMethod(), m2.getInvocable().getHandlingMethod(), runtimeResource.getRegex()));
+            boolean interfaceM1 = isInterface(m1);
+            boolean interfaceM2 = isInterface(m2);
+            // Fails when both are interfaces or both are not interfaces
+            if (interfaceM1 == interfaceM2) {
+                // fatal
+                Errors.fatal(runtimeResource, LocalizationMessages.AMBIGUOUS_FATAL_RMS(httpMethod, m1.getInvocable()
+                        .getHandlingMethod(), m2.getInvocable().getHandlingMethod(), runtimeResource.getRegex()));
+            }
         } else if ((producesFails && consumesOnlyIntersects)
                 || (consumesFails && producesOnlyIntersects)
                 || (consumesOnlyIntersects && producesOnlyIntersects)) {
@@ -122,6 +127,10 @@ private void checkIntersectingMediaTypes(
         }
     }
 
+    private boolean isInterface(ResourceMethod m1) {
+        return m1.getData().getInvocable().getHandler().getHandlerClass().isInterface();
+    }
+
     private static final List<MediaType> StarTypeList = Arrays.asList(new MediaType("*", "*"));
 
     private List<MediaType> getEffectiveInputTypes(final ResourceMethod resourceMethod) {
diff --git a/tests/e2e-server/src/test/java/org/glassfish/jersey/tests/e2e/server/Issue4780Test.java b/tests/e2e-server/src/test/java/org/glassfish/jersey/tests/e2e/server/Issue4780Test.java
new file mode 100644
index 0000000000..846789b8b8
--- /dev/null
+++ b/tests/e2e-server/src/test/java/org/glassfish/jersey/tests/e2e/server/Issue4780Test.java
@@ -0,0 +1,118 @@
+/*
+ * Copyright (c) 2021 Oracle and/or its affiliates. All rights reserved.
+ *
+ * This program and the accompanying materials are made available under the
+ * terms of the Eclipse Public License v. 2.0, which is available at
+ * http://www.eclipse.org/legal/epl-2.0.
+ *
+ * This Source Code may also be made available under the following Secondary
+ * Licenses when the conditions for such availability set forth in the
+ * Eclipse Public License v. 2.0 are satisfied: GNU General Public License,
+ * version 2 with the GNU Classpath Exception, which is available at
+ * https://www.gnu.org/software/classpath/license.html.
+ *
+ * SPDX-License-Identifier: EPL-2.0 OR GPL-2.0 WITH Classpath-exception-2.0
+ */
+
+
+package org.glassfish.jersey.tests.e2e.server;
+
+import static org.junit.Assert.assertEquals;
+
+import javax.ws.rs.GET;
+import javax.ws.rs.Path;
+import javax.ws.rs.core.Response;
+
+import org.glassfish.jersey.server.ResourceConfig;
+import org.glassfish.jersey.server.model.ModelValidationException;
+import org.glassfish.jersey.test.JerseyTest;
+import org.junit.Test;
+
+public class Issue4780Test {
+
+    // 1 interface and 1 implementation having same @Path
+    @Test
+    public void resource1() throws Exception {
+        JerseyTest test = new JerseyTest(new ResourceConfig(Resource1_1.class, IResource1_2.class)) {};
+        try {
+            test.setUp();
+            Response response = test.target().path("/resource1").request().get();
+            response.bufferEntity();
+            assertEquals(response.readEntity(String.class), 200, response.getStatus());
+        } finally {
+            test.tearDown();
+        }
+    }
+
+    // 2 interfaces having same @Path
+    @Test(expected = ModelValidationException.class)
+    public void resource2() throws Exception {
+        JerseyTest test = new JerseyTest(new ResourceConfig(IResource2_1.class, IResource2_2.class)) {};
+        try {
+            test.setUp();
+        } finally {
+            test.tearDown();
+        }
+    }
+
+    // 2 classes having same @Path
+    @Test(expected = ModelValidationException.class)
+    public void resource3() throws Exception {
+        JerseyTest test = new JerseyTest(new ResourceConfig(Resource3_1.class, Resource3_2.class)) {};
+        try {
+            test.setUp();
+        } finally {
+            test.tearDown();
+        }
+    }
+
+    @Path("")
+    public static class Resource1_1 implements IResource1_2 {
+        @GET
+        @Path("/resource1")
+        @Override
+        public String get() {
+            return "";
+        }
+    }
+
+    @Path("")
+    public static interface IResource1_2 {
+        @GET
+        @Path("/resource1")
+        String get();
+    }
+
+    @Path("")
+    public static interface IResource2_1 {
+        @GET
+        @Path("/resource2")
+        String get();
+    }
+
+    @Path("")
+    public static interface IResource2_2 {
+        @GET
+        @Path("/resource2")
+        String get();
+    }
+
+    @Path("")
+    public static class Resource3_1 {
+        @GET
+        @Path("/resource3")
+        public String get() {
+            return "";
+        }
+    }
+
+    @Path("")
+    public static class Resource3_2 {
+        @GET
+        @Path("/resource3")
+        public String get() {
+            return "";
+        }
+    }
+
+}