Background: While the majority of healthcare in the US is provided in community hospitals, the epidemiology and treatment of bloodstream infections in this setting is unknown. Methods and Findings: We undertook this multicenter, retrospective cohort study to 1) describe the epidemiology of bloodstream infections (BSI) in a network of community hospitals and 2) determine risk factors for inappropriate therapy for bloodstream infections in community hospitals. 1,470 patients were identified as having a BSI in 9 community hospitals in the southeastern US from 2003 through 2006. The majority of BSIs were community-onset, healthcare associated (n = 823, 56%); 432 (29%) patients had community-acquired BSI, and 215 (15%) had hospital-onset, healthcare-associated BSI. BSIs due to multidrug-resistant pathogens occurred in 340 patients (23%). Overall, the three most common pathogens were S. aureus (n = 428, 28%), E. coli (n = 359, 24%), coagulase-negative Staphylococci (n = 148, 10%), though type of infecting orgaism varied by location of acquisition (e.g., community-acquired). Inappropriate empiric antimicrobial therapy was given to 542 (38%) patients. Proportions of inappropriate therapy varied by hospital (median = 33%, range 21-71%). Multivariate logistic regression identified the following factors independently associated with failure to receive appropriate empiric antimicrobial therapy: hospital where the patient received care (p,0.001), assistance with $3 ADLs (p = 0.005), Charlson score (p = 0.05), community-onset, healthcare-associated infection (p = 0.01), and hospital-onset, healthcareassociated infection (p = 0.02). Important interaction was observed between Charlson score and location of acquisition. Conclusions: Our large, multicenter study provides the most complete picture of BSIs in community hospitals in the US to date. The epidemiology of BSIs in community hospitals has changed: community-onset, healthcare-associated BSI is most common, S. aureus is the most common cause, and 1 of 3 patients with a SI receives inappropriate empiric antimicrobial therapy. Our data suggest that appropriateness of empiric antimicrobial therapy is an important and needed performance metric for physicians and hospital stewardship programs in community hospitals