We conducted a five-year prospective controlled study of prophylaxis of Staphylococcus aureus nasal carriage and infection among patients in a hemodialysis unit. Carriers tended to have chronic colonization with a single phage type. S. aureus infections occurred significantly more frequently in carriers than in noncarriers and, in 93 percent of the infected carriers, were caused by the same phage type as that carried in the nares. Neither intravenous vancomycin nor topical bacitracin was found to be efficacious in eradicating nasal carriage. However, oral rifampin given for five days decreased S. aureus carriage over a one-month follow-up period, but within three months colonization of the nares recurred in most carriers, often with an S. aureus of the original phage type. Carriers were then randomly assigned to receive either rifampin or no prophylaxis. Rifampin was readministered at three-month intervals if culture of the anterior nares yielded S. aureus. Infections with S. aureus occurred significantly more frequently in carriers given no prophylaxis than in those given a full course of rifampin. S. aureus resistant to rifampin was isolated from the anterior nares of four patients, but these isolates were not implicated in any infections. The incidence of infection at the dialysis access site, skin, and soft tissue of patients on hemodialysis can be decreased by interventions directed at nasal carriage of S. aureus.