OBJECTIVES: To describe the epidemiology of nosocomial coagulase-negative staphylococci (CoNS) bacteremia and to evaluate the clinical significance of a single blood culture positive for CoNS. DESIGN: A 3-year retrospective cohort study based on data prospectively collected through hospital-wide surveillance. Bacteremia was defined according to CDC criteria, except that a single blood culture growing CoNS was not systematically considered as a contaminant. All clinically significant blood cultures positive for CoNS nosocomial bacteremia were considered for analysis. SETTING: A large university teaching hospital in Geneva, Switzerland. RESULTS: A total of 2,660 positive blood cultures were identified. Of these, 1,108 (41.7%) were nosocomial; CoNS were recovered from 411 nosocomial episodes (37.1%). Two hundred thirty-four episodes of CoNS bacteremia in the presence of signs of sepsis were considered clinically relevant and analyzed. Crude mortality and associated mortality were 24.4% and 12.8%, respectively. Associated mortality was similar among patients with one positive blood culture and those with two or more (16.2% vs 10.8%, respectively; P =.3). Mortality rates after bacteremia for patients with a single positive blood culture and for those with two or more were 15.3% and 7.0%, respectively, at day 14 (RR, 2.2; CI95, 0.87-5.46) and 20.8% and 11.3%, respectively, at day 28 (RR, 1.9; CI95, 0.9-3.8). On multivariate analysis, only age and a rapidly fatal disease were independently associated with death. CONCLUSION: CoNS bacteremia harbor a significant mortality and a single positive blood culture in the presence of signs of sepsis should be considered as clinically relevant.