Enterococcal endocarditis in man is traditionally treated with penicillin and an aminoglycoside. Whether penicillin alone is adequate has not been fully evaluated. Experimental enterococcal endocarditis (EEE) in male New Zealand rabbits, when untreated, was fatal in all animals within 2 weeks. When crystalline penicillin G was given at 30,000 U/day in three equally divided doses, the fatality rate was 63.3%; when the dosage was increased to 600,000 U/day, the mortality was 37.5%, demonstrating the ineffectiveness of crystalline penicillin alone in EEE. Procaine penicillin at 300,000 U/day given as a single dose provided increased protection, but was still associated with unacceptably high mortality (17.5%). A higher dose level, 600,000 U/day, of procaine penicillin protected all animals with EEE. High and sustained levels of penicillin in the serum and the myocardium cured enterococcal endocarditis in rabbits.