The natural history and outcome of Staphylococcus aureus bacteremia in patients with acute leukemia were studied over a 10 year period at the Baltimore Cancer Research Program. There were 370 patients at risk; 32 (9 percent) had 37 episodes. Granulocytopenia (less than 1,000/microliters) was present in 95 percent of the episodes. The sites of origin of bacteremia were identified in 32 episodes and were usually the skin and lower respiratory tract. Initially, broad-spectrum antimicrobials were used empirically in 30 episodes and specific antistaphylococcal therapy was used in the remaining seven episodes. The median duration of therapy was 14 days of intravenous therapy and seven days of oral therapy, a total of 21 days. There was improvement during therapy in 31 of the 37 episodes (83 percent) although, among the subgroup of six patients with shock, only one improved (p less than 0.001). There was no clinical or postmortem evidence of endocarditis in any patient. Since endocarditis complicating Staph. aureus bacteremia appears to be rare in patients with acute leukemia, a shorter course of therapy than that usually recommended for endocarditis may be justified.