diff --git a/NAMESPACE b/NAMESPACE
index d80abdf..a1a499a 100644
--- a/NAMESPACE
+++ b/NAMESPACE
@@ -329,6 +329,8 @@ importFrom(graphics,par)
 importFrom(graphics,title)
 importFrom(methods,as)
 importFrom(methods,is)
+importFrom(methods,isGeneric)
+importFrom(methods,selectMethod)
 importFrom(stats,cor)
 importFrom(stats,median)
 importFrom(stats,quantile)
diff --git a/R/bit64-package.R b/R/bit64-package.R
index dbac467..e693715 100644
--- a/R/bit64-package.R
+++ b/R/bit64-package.R
@@ -704,7 +704,7 @@
 #'   ramsort ramsortorder repeat.time setattr shellorder shellsort
 #'   shellsortorder still.identical
 #' @importFrom graphics barplot par title
-#' @importFrom methods as is
+#' @importFrom methods as is isGeneric selectMethod
 #' @importFrom stats cor median quantile
 #' @importFrom utils head packageDescription strOptions tail getS3method
 #' @export : %in% is.double match order print.cache rank
diff --git a/R/setops64.R b/R/setops64.R
index 78deb9a..786ad0c 100644
--- a/R/setops64.R
+++ b/R/setops64.R
@@ -31,9 +31,13 @@
 #' @export
 #' @rdname sets
 union = function(x, y) {
+  if ((isS4(x) || isS4(y)) && isGeneric("union")) {
+    s4_intersect = selectMethod("union", list(x=class(x), y=class(y)))
+    return(s4_intersect(x, y))
+  }
   if (!(is.integer64(x) || is.integer64(y)))
     return(base::union(x, y))
-  
+
   target_class = target_class(list(x, y))
   # try using the benefit of integer64 caching, if possible. I.e. call unique() before as().
   x = unique(x)
@@ -60,9 +64,13 @@ union = function(x, y) {
 #' @rdname sets
 intersect = function(x, y) {
   if (is.null(x) || is.null(y)) return(NULL)
+  if ((isS4(x) || isS4(y)) && isGeneric("intersect")) {
+    s4_intersect = selectMethod("intersect", list(x=class(x), y=class(y)))
+    return(s4_intersect(x, y))
+  }
   if (!(is.integer64(x) || is.integer64(y)))
     return(base::intersect(x, y))
-  
+
   target_class = target_class(list(x, y))
   x = unique(x)
   class_x = class(x)[1L]
@@ -109,6 +117,10 @@ setequal = function(x, y) {
 #' @export
 #' @rdname sets
 setdiff = function(x, y) {
+  if ((isS4(x) || isS4(y)) && isGeneric("setdiff")) {
+    s4_intersect = selectMethod("setdiff", list(x=class(x), y=class(y)))
+    return(s4_intersect(x, y))
+  }
   if (!(is.integer64(x) || is.integer64(y)))
     return(base::setdiff(x, y))
   
diff --git a/tests/testthat/test-setops64.R b/tests/testthat/test-setops64.R
index 91c6ccb..a3386d6 100644
--- a/tests/testthat/test-setops64.R
+++ b/tests/testthat/test-setops64.R
@@ -320,3 +320,55 @@ test_that("is.element works (additional cases)", {
   expect_true(is.element(NA_integer64_, NA))
 
 })
+
+test_that("S4 dispatch still happens for classes extending integer64 (#301)", {
+  methods::setClass("TestS4", representation(data="integer"))
+
+  delete_intersect_generic = !methods::isGeneric("intersect")
+  suppressMessages(methods::setGeneric("intersect"))
+  delete_union_generic = !methods::isGeneric("union")
+  suppressMessages(methods::setGeneric("union"))
+  delete_setdiff_generic = !methods::isGeneric("setdiff")
+  suppressMessages(methods::setGeneric("setdiff"))
+
+  methods::setMethod(
+    "intersect",
+    signature=c("TestS4", "integer64"),
+    function(x, y) "Successfully routed to S4 method!"
+  )
+  methods::setMethod(
+    "union",
+    signature=c("TestS4", "integer64"),
+    function(x, y) "Successfully routed to S4 method!"
+  )
+  methods::setMethod(
+    "setdiff",
+    signature=c("TestS4", "integer64"),
+    function(x, y) "Successfully routed to S4 method!"
+  )
+  withr::defer({
+    methods::removeMethod("setdiff", signature=c("TestS4", "integer64"))
+    methods::removeMethod("union", signature=c("TestS4", "integer64"))
+    methods::removeMethod("intersect", signature=c("TestS4", "integer64"))
+    methods::removeClass("TestS4")
+    if (delete_setdiff_generic) methods::removeGeneric("setdiff")
+    if (delete_union_generic) methods::removeGeneric("union")
+    if (delete_intersect_generic) methods::removeGeneric("intersect")
+  })
+
+  # Instantiate test objects
+  x = methods::new("TestS4", data = 1L)
+  y = as.integer64(2L)
+
+  expect_identical(intersect(x, y), "Successfully routed to S4 method!")
+  expect_identical(union(x, y), "Successfully routed to S4 method!")
+  expect_identical(setdiff(x, y), "Successfully routed to S4 method!")
+  # NB: nanoival class is "complex64" -- it kludges complex to be a pair
+  #   of integer64 vectors, but there is no complex64 class, so it just
+  #   shows up on the inheritance chain as 'complex' --> need to ensure
+  #   S4 gets invoked when possible even if the inputs don't directly test
+  #   as being is("integer64").
+  expect_identical(intersect(x, x), "Successfully routed to S4 method!")
+  expect_identical(union(x, x), "Successfully routed to S4 method!")
+  expect_identical(setdiff(x, x), "Successfully routed to S4 method!")
+})