Propionibacterium species rarely cause infective endocarditis. When identified in blood cultures, they may be inappropriately disregarded as skin flora contaminants. The purpose of this study was to characterize the clinical presentation and management of endocarditis due to Propionibacterium species. All cases of endocarditis due to Propionibacterium species that were treated at the Mayo Clinic, Rochester, USA were retrospectively reviewed, and the English language medical literature was searched for all previously published reports. Seventy cases, which included eight from the Mayo Clinic, were identified (clinical details were available for only 58 cases). The median age of patients was 52 years, and 90% were males. In 79% of the cases, the infection involved prosthetic material (39 prosthetic valves, one left ventricular Teflon patch, one mitral valve ring, one pulmonary artery prosthetic graft, three pacemakers, and one defibrillator). Blood cultures were positive in 62% of cases. All 22 cases with negative blood cultures were microbiologically confirmed by either positive valve tissue cultures (n = 21) or molecular methods (n = 1). Endocarditis was complicated by abscess formation in 36% of cases. The majority (81%) of patients underwent surgery, either for valve replacement and debridement of a cardiac abscess, or removal of an infected device. Crude in-hospital mortality was 16%. The median duration of postoperative antibiotic treatment was 42 days. Patients were commonly treated with a penicillin derivative alone or in combination with gentamicin. On the basis of the above data, it is recommended that infective endocarditis should be strongly suspected when Propionibacterium species are isolated from multiple blood cultures, particularly in the presence of a cardiovascular device.