A prospective, observational study of 110 patients with serious infections due to Enterococcus spp. in 6 university and community teaching hospitals in Connecticut was conducted to define the epidemiology of community and nosocomial serious enterococcal infections and to determine risk factors, including antibiotic resistances, that contribute to outcome. Serious community and nosocomial enterococcal infections involved a variety of sites, and antibiotic resistance was common. Types of infection by major organ system were cardiovascular, 54% (catheter-related bacteremia 28%, primary bacteremia 18%, endocarditis 6%, septic thrombophlebitis 1%); intra-abdominal, 13% (including cholangitis, 6%); renal, 13%; skin and soft tissue, 5%; bone and joint, 4%; pleuropulmonary, 4%; central nervous system, 3%; deep surgical wound, 3%; and endometritis, 2%. Sixty-one percent of infections were nosocomial; 48% of these occurred in the intensive care unit. Enterococcus faecium was responsible for 20% of all infections. Antibiotic resistances among the infections included high-level gentamicin resistance (26%), ampicillin resistance (10%), and vancomycin resistance (8%). Clinical cure was achieved in 64% of patients; 6.8% of patients relapsed, 6.8% had recurrence of the infection with a different pathogen, and overall mortality was 23%. Ampicillin resistance and a high acute physiology and chronic health evaluation (APACHE) II score were highly predictive of lack of cure.