Background: Infections occurring among outpatients having recent contact with the health care system have been termed health care-associated infections. The objective of this study was to analyze the impact of health care-associated status on effectiveness of initial therapy in hospitalized patients with bloodstream infections. Methods: Prospective cohort study of adults with bloodstream infections at 3 North Carolina hospitals. Bloodstream infection was defined as health care-associated if it occurred within the first 48 hours after hospitalization and if patients had 1 of the following characteristics: had received home health services, outpatient intravenous therapy, or outpatient renal dialysis in the 30 days prior to hospital admission; had been hospitalized within 90 days prior to admission; or lived in a long-term care facility. Results: Of 466 bloodstream infections, 132 (28%) were community-acquired, 178 (38%) were health care-associated, and 156 (33%) were nosocomial. Multivariable logistic regression using community-acquired status as a reference identified health care-associated status (odds ratio, 3.1; 95% confidence interval, 1.6-6.1) and nosocomial status (odds ratio, 4.3; 95% confidence interval, 2.2-8.3) as independent predictors of ineffective initial antibiotic therapy. Among health care-associated characteristics, hospitalization in the 90 days prior to admission was independently associated with ineffective initial therapy (odds ratio, 2.4; 95% confidence interval, 1.4-4.2). Conclusions: Among patients treated in the hospital for bloodstream infection, health care-associated status was an independent predictor of ineffective initial antibiotic therapy. Hospitalization within 90 days prior to hospital admission was the component of health care-associated status most strongly associated with ineffective initial therapy.