Despite the use of oral anticoagulation in patients with prosthetic heart valves, persistent thromboembolism over time warrants a search for improved methods of prevention. Thus, patients receiving 1 or more mechanical prosthetic heart valves were randomized to therapy with warfarin plus dipyridamole (400 mg/day) or warfarin plus aspirin (500 mg/day) on the basis of location and type of valve and surgeon, and followed up with a concurrent, nonrandomized control group taking warfarin alone. In 534 patients followed up 1,319 patient-years, excessive bleeding (necessitating blood transfusion or hospitalization) was noted in the warfarin plus aspirin group (23 of 170 [14%], or 6.0/100 patient-years) compared with warfarin plus dipyridamole (7 of 181 [4%], or 1.6/100 patient-years, p less than 0.001), or warfarin alone (9 of 183 [5%], or 1.8/100 patient-years, p less than 0.001). A trend was evident toward a reduction in thromboembolism in the warfarin plus dipyridamole group (2 of 181 [1%], or 0.5/100 patient-years) as compared with warfarin plus aspirin (7 of 170 [4%], or 1.8/100 patient-years), or warfarin alone (6 of 183 [4%], or 1.2/100 patient-years). Adequacy of anticoagulation (based on 12,720 prothrombin time determinations) was similar in all 3 groups with 65% of prothrombin times in the therapeutic range (1.5 less than or equal to prothrombin time/control less than or equal to 2.5), 30% too low, and 5% too high. Warfarin plus aspirin therapy resulted in excessive bleeding and is contraindicated. Longer follow-up study is needed to determine whether further separation of the incidence of thromboembolism can be detected.