Over the last two decades, the optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia has become the subject of controversy. A review of the literature revealed an occasional association between relapse of the infection and a short course of therapy (less than 10 days of iv antibiotic therapy). From records kept between 1983 and 1989 at the University of Florida's affiliated hospitals, we identified 55 patients with catheter-related S. aureus bacteremia. Nine patients (16%) developed acute early complications (e.g., endocarditis or osteomyelitis) while receiving antibiotics. The results of multivariate analysis showed that an early complicated course was characterized by fever and/or bacteremia that persisted for greater than 3 days after catheter removal (P = .02). The remaining 46 patients were followed up for at least 3 months. During follow-up, three of the 18 patients treated for less than 10 days with iv antibiotics developed relapsing septicemia, whereas none of the 28 patients treated for a longer period developed this condition (P = .05). Fever and/or bacteremia that persists for greater than 3 days after catheter removal and initiation of antibiotic therapy suggests an acutely complicated course requiring prolonged treatment. The duration of iv antibiotic therapy in uncomplicated cases should not be less than 10 days but need not be greater than 2 weeks.