Penicillin G alone is generally recommended for the treatment of infective endocarditis caused by Streptococcus bovis because clinical isolates of S bovis are represented as being uniformly and markedly susceptible to penicillin G. However, two strains of S bovis recovered from two patients with bacterial endocarditis were resistant to the lethal effect of penicillin G. Combination therapy, cefazolin sodium and gentamicin sulfate in patient 1 and penicillin G and gentamicin in patient 2, was necessary; synergy, as manifested by lethal activity against the infecting strains, was demonstrated in the laboratory. We stress the need to determine the minimal lethal concentration of penicillin G for clinical isolates of S bovis. Until such information is available, particularly in life-threatening infections, combination drug therapy, consisting of an aminocyclitol added to a beta-lactam antimicrobic, should be used.