Whether antibiotic prophylaxis can prevent bacterial endocarditis is hotly debated. In an attempt to settle this issue, we have assessed the efficacy of prophylaxis for bacterial endocarditis on native valves in a nationwide, case-control study in the Netherlands. Cases were patients with known cardiac disease in whom endocarditis developed within 180 days of a medical or dental procedure for which prophylaxis was indicated. Of a total of 438 patients with endocarditis diagnosed during 2 years, 48 were eligible for the study. Controls were patients with the same cardiac status in whom endocarditis did not develop within 180 days of a similar procedure; of a total of 889 controls from five hospitals, 200 were eligible. Overall, about 1 in 6 patients in both groups had received prophylaxis. The best estimate of protective efficacy was 49% for first-ever endocarditis occurring within 30 days of a procedure. Endocarditis developed within 30 days of a procedure in only 13% of patients with a previously diagnosed heart lesion which predisposed to the disease. The findings suggest that strict adherence to generally accepted recommendations for prophylaxis might do little to decrease the total number of patients with endocarditis in the community.