A 42 year old heroin addict with Staphylococcus aureus endocarditis of the mitral valve was treated with clindamycin phosphate, 600 mg intramuscularly, every 6 hours. The initial clinical response was excellent and blood cultures became negative. On the 26th day of clindamycin therapy, fever developed and six blood cultures taken during a 72 hour period grew Staph. aureus. The patient was subsequently cured with a six week course of nafcillin plus gentamicin followed by cloxacillin. The Staph. aureus isolated before clindamycin therapy and during relapse phage-typed 29/52/52A/79/80 and was resistant to penicillin G. The susceptibility of both Staph. aureus isolates to 19 antibiotics was unchanged. However, the Stahph. aureus developed marked resistance to clindamycin, lincomycin and erythromycin, to which the original isolate was susceptible. The resistance to clindamycin and lincomycin was heterogeneous whereas the entire cell population became homogeneously highly resistant to erythromycin. These antibiotics were not inactivated in vitro by the rapidly growing resistant Staph. aureus. The most likely site of resistance was at the 50 S subunit of the bacterial ribosome.