Staphylococcus aureus is one of the leading agents of nosocomial infection among adult patients. The aim of this study was to determine the predisposing factors and secondary complications of Staphylococcus aureus septicemia (SAS) in non neutropenic patients, as well as the predictors of the outcome in non neutropenic patients with SAS. We performed a retrospective study of 56 cases of SAS that occurred from January 1997 through June 2001 in patients hospitalized in medical wards at the Policlinico Umberto I, "La Sapienza" University of Rome; we excluded surgical patients and those admitted to the intensive care unit. The median age was 61.9 years (range 24-89 years), 29 (51%) patients were male, and infection was hospital-acquired in 83.5% of cases. Metastatic infections were found in 12 patients (21.4%), with 6 (10.7%) developing infectious endocarditis; the relapse rate was 8.9%; 30.3% of Staphylococcus aureus isolates were methicillin-resistant. The overall mortality was 41% and the attributable mortality 28.5%. Twenty-nine patients who developed metastatic infections or died for sepsis were compared with 27 patients who did not develop complications. At univariate analysis, the following factors were associated with a complicated course: delay to adequate antibiotic therapy (2.46 vs 1.15 days, p < 0.03), persistent Staphylococcus aureus bacteremia during antibiotic therapy (3.56 vs 1.51 days, p = 0.01), septic shock (58.6 vs 3.7%, p < 0.002), bacteremic pneumonia as the source of bacteremia (17.2 vs 0%, p = 0.02), and the increased severity of illness at the onset of SAS as evaluated using an "illness score" (4.2 vs 2.1, p < 0.002). At multivariate analysis, septic shock (p < 0.01) and delay to adequate antibiotic therapy (p = 0.05) were confirmed as associated with a complicated outcome. SAS in non neutropenic patients is associated with significant morbidity consequent to a high rate of metastatic infectious disease and with a considerable related mortality.