BACKGROUND The emergence of viridans group streptococci that are relatively or fully resistant to penicillin is increasingly being recognized worldwide, but only a scant number of penicillin-resistant isolates have been described as a cause of infective endocarditis. Because of the paucity of data, it has been difficult to define optimal treatment regimens for this syndrome. Thus, recommendations for therapy have largely been made on the basis of consensus opinion. METHODS We retrospectively identified a cohort of patients with infective endocarditis due to penicillin-resistant viridans group streptococci who were seen at the Mayo Clinic (Rochester, MN) between January 1967 and April 2006. Demographic characteristics, clinical features, treatment regimens, and outcomes were analyzed. Mean values are shown with standard deviations. RESULTS Twenty-nine patients were identified over the 38.5-year study period. Nineteen patients with native valve endocarditis were cured; 9 of these 19 patients received a 2.3+/-0.4-week antibiotic regimen consisting of penicillin and an aminoglycoside, and 8 of these 19 patients received treatment courses of 5.1+/-1.4 weeks' duration that consisted of either a bimodal combination regimen with a penicillin or ceftriaxone and an aminoglycoside or ceftriaxone monotherapy. Nine of 10 patients with prosthetic valve infection were cured with 4.1+/-0.6-week regimens that consisted of either a combination regimen or monotherapy with vancomycin or ceftriaxone. Mean duration of follow-up after hospital discharge was 9.1 years. CONCLUSIONS Outcomes of this relatively large population of patients with endocarditis with a prolonged duration of follow-up indicate that the application of current treatment guidelines should be successful in most patients.