Fifty-two cases of apparent endocarditis prophylaxis failure were reported to a national registry established by the American Heart Association (AHA). Mitral valve prolapse was the single most common underlying cardiac lesion (17 cases, 33%), followed by various congenital abnormalities (15 cases, 29%) and rheumatic heart disease (11 cases, 21%). Ten patients (19%) had prosthetic valve endocarditis. Forty-eight cases (92%) occurred after a dental procedure. Symptoms began within two weeks after the procedure suspected to have caused endocarditis in 50% and within five weeks in 79%. Thirty-nine cases (75%) were caused by viridans streptococci and seven (14%) by Staphylococcus aureus. Most patients received oral penicillin as prophylaxis. Only six patients (12%) received regimens currently recommended by the AHA. In 27 (63%) of the 43 cases for which antimicrobial susceptibility data were available, the infecting microorganism was sensitive to the antibiotic(s) used for prophylaxis. After diagnosis of endocarditis, the prognosis for bacteriologic cure was good; 47 patients (90%) were cured, of whom seven underwent valve replacement. These data indicate that endocarditis prophylaxis failures may be more common than was previously believed and that failures occur even when the infecting organism is susceptible to the antibiotics used. Most antimicrobial regimens used in patients with prophylaxis failures did not conform to current recommendations.