We compared the efficacy and complications of anticoagulation with warfarin in 258 patients with prosthetic heart valves treated with regimens of "moderate intensity" (prothrombin-time ratio, 1.5; international normalized ratio, 2.65) or "high intensity" (prothrombin-time ratio, 2.5; international normalized ratio, 9) in a prospective, randomized study. The two patient groups were followed up for 421 patient-years and 436 patient-years, respectively. Eleven patients were lost to follow-up. Thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 episodes per 100 patient-years, respectively), but there was a total of 6.2 bleeding episodes per 100 patient-years in the moderate-intensity group, as compared with 12.1 episodes in the high-intensity group (P less than 0.002). There were 5.2 episodes of minor bleeding per 100 patient-years in the moderate-intensity group, as compared with 10.1 episodes in the high-intensity group (P less than 0.01). Major bleeding was also more common in the high-intensity group (2.1 episodes per 100 patient-years--including the only two fatal hemorrhages--as compared with 0.95 episode in the moderate-intensity group), but the difference was not statistically significant. We conclude that a moderate anticoagulant effect (prothrombin-time ratio, about 1.5) in patients with a mechanical prosthetic heart valve offers protection equivalent to that of more intensive therapy, but at a significantly lower risk.