Polycythemia vera (PV) is associated with increased risk of thrombosis and hemorrhage. Aspirin, recommended for primary thromboprophylaxis, is often combined with anticoagulants during management of acute thrombotic events. The safety of dual antiplatelet and anticoagulant therapy is not established in PV. In a prospective, observational study, 2,510 patients with PV were enrolled at 227 sites in the United States. Patients were monitored for the development of hemorrhage and thrombosis after enrollment. A total of 1,602 patients with PV received aspirin with median follow-up of 2.4 years (range, 0-3.6 years). The exposure-adjusted rate of all hemorrhages in patients receiving aspirin alone was 1.40 per 100 patient-years (95% confidence interval [CI]: 0.99-1.82). The combination of aspirin plus anticoagulant was associated with an incidence of hemorrhage of 6.75 per 100 patient-years (95% CI: 3.04-10.46). The risk of hemorrhage was significantly greater in patients receiving the combination of aspirin and anticoagulant compared with aspirin alone (total hemorrhages, hazard ratio [HR]: 5.83; 95% CI: 3.36-10.11; P<0.001; severe hemorrhage, HR: 7.49; 95% CI: 3.02-18.62; P<0.001). Periods of thrombocytosis (>600×109/L) were associated with an increased risk of hemorrhage (HR: 2.25; 95% CI: 1.16- 4.38; P=0.02). Rates of hemorrhage were similar for aspirin in combination with warfarin or direct-acting oral anticoagulants. We conclude that the combination of aspirin and anticoagulants is associated with significantly increased risk of hemorrhage in patients with PV (clinicaltrials gov. Identifier: NCT02252159).