Risk factors for the development of prosthetic valve endocarditis (PVE) were analyzed in 2642 patients undergoing initial valve replacement at the Massachusetts General Hospital from 1975 to 1982. Follow-up was available for 2608 patients (98.7%); the mean length of follow-up was 39.8 months. PVE developed in 116 patients (4.4%). The actuarial risk of PVE was 3.1% at 12 months and 5.7% at 60 months. A Cox model was used to identify risk factors for PVE. Recipients of multiple valves had a higher risk of PVE than single valves (p = .01). There was no difference in the risk of PVE for patients receiving aortic valves vs those receiving mitral valves. Recipients of mechanical valves had a higher risk of PVE than recipients of porcine valves in the first 3 months after surgery (p = .02), but the risk of PVE was higher for porcine valve recipients 12 months or more after surgery (p = .004). Despite this difference in the time course of development of PVE, there was no significant difference in the cumulative risk of PVE by 5 years of follow-up between mechanical and porcine valve recipients. Male sex was a risk factor for PVE within 12 months of aortic valve replacement (p = .008) but not thereafter; sex did not influence the risk of PVE after mitral valve replacement. Older patients had a higher risk of late PVE after multiple (p = .04) or mitral valve replacement (p = .08), but not after aortic valve replacement.