Lupus anticoagulants (LA) can cause acquired activated protein C resistance (APC-R), but the clinical significance is unclear. To investigate thrombosis and acquired APC-R in patients with LA, we enrolled all 132 patients undergoing hypercoagulability testing with positive LA results and in whom APC-R (with factor V-deficient plasma) was performed during a 2.5-year period. Among 121 patients without factor V Leiden, 24.0% had acquired APC-R; retrospective and prospective (mean follow-up, 2.0 years) thrombotic events were analyzed. The distribution of venous vs arterial thrombosis was different for APC-R vs no APC-R (P = .0064). The majority (19/29 [66%]) with acquired APC-R experienced venous thrombosis, whereas a minority experienced arterial thrombosis (9/29 [31%]; P = .017). The opposite pattern occurred among patients without APC-R (arterial thrombi more common than venous thrombi). After excluding thrombotic events more than 5 years from a positive LA test, venous thrombosis occurred in 62% with (18/29) vs 32% without (29/92) APC-R (P = .0045); and arterial thrombosis in 28% with (8/29) vs 51% without (47/92) APC-R (P = .033). Patients with acquired APC-R due to LA had more venous thrombosis than did patients with LA without APC-R and experienced venous more often than arterial thrombosis.