The efficacy of imipenem alone or in association with gentamicin against Staphylococcus aureus experimental endocarditis was compared to the efficacy of cloxacillin alone or in association with gentamicin. Parenteral treatment was started 24 h after intravenous bacterial challenge of rats with catheter-induced aortic valve vegetations. The cloxacillin MIC and MBC for Staph. aureus were 0.125 and 32 mg/l and the imipenem MIC and MBC 0.008 and 8 mg/l, respectively. In-vitro killing curves showed a synergistic effect between cloxacillin and gentamicin, and an additive effect between imipenem and gentamicin. Only large doses of cloxacillin (400 mg/kg tid) (producing serum levels above those obtained after intravenous injection of 2 g in man) achieved results comparable to those of imipenem 80 mg/kg tid (producing serum levels similar to those obtained after an intravenous dose of 750 mg in man) in reducing the bacterial numbers in vegetations after 3 and 5 days of treatment. There was a significantly greater reduction of bacterial numbers in vegetations after treatment with the association of cloxacillin and gentamicin than with cloxacillin alone. In contrast, the addition of gentamicin to imipenem did not improve significantly the results of treatment with imipenem alone, but imipenem alone was as good as the combination cloxacillin and gentamicin after 5 days of treatment. We conclude that imipenem is a highly bactericidal drug in this animal model, worth considering for clinical trials in the treatment of Staph. aureus infections.