Seven patients with severe methicillin-resistant Staphylococcus aureus infections (5 with bacterial endocarditis, 1 with mediastinitis and 1 with meningitis and septicaemia) were treated with rifampicin combined with vancomycin in 6 cases and with gentamicin in 1 case. The 7 strains initially isolated from haemocultures were resistant to methicillin and sensitive to rifampicin. In 4 of these patients (3 of whom received vancomycin and 1 gentamicin) clinical and bacteriological failure was observed, with selection of rifampicin-resistant mutants. Bactericidal activity was always mediocre in both serum and cerebrospinal fluid, with insufficient vancomycin and gentamicin concentrations in 3 patients. An in vitro study of the combined antibiotics by the chequer-board method suggested antagonism in 3 of these 4 cases. Thus, in spite of its excellent activity and unquestionable effectiveness, rifampicin should be used with caution in severe staphylococcal infections.