From 1975 through 1978 isolates from 21 of 230 (9%) Staphylococcus aureus bacteremias were resistant to gentamicin and clindamycin. Gentamicin- and clindamycin-resistant S aureus (GCRS) accounted for 23% of all S aureus isolates from 1977 compared with 2 to 6% in the two years immediately preceding, and the year following 1977. When compared with patients with gentamicin- and clindamycin-sensitive S aureus (GCSS) from 1977, GCRS were more often isolated from patients who acquired their infections in the hospital, particularly in the intensive care unit. A significant association existed between prior or concurrent therapy with gentamicin and/or clindamycin and the isolation of GCRS. Infection with GCRS was associated with a 73% mortality rate versus 28% with GCSS. GCRS were susceptible to oxacillin, cephalothin, tetracycline, and vancomycin. GCRS were resistant to kanamycin and tobramycin but were susceptible to amikacin (median MIC of GCRS, 4.0 microgram/ml). Multiple bacteriophage types of S aureus were involved, and resistance appeared to be plasmid-mediated. A survey of antibiotic usage showed that in comparison to January 1977, a mikacin usage increased and gentamicin usage decreased in March 1979. Because of the popularity of the combination of clindamycin and gentamicin for therapy of life-threatening infections, clinicians should be aware of potential gentamicin- and clindamycin-resistance in S aureus.