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Objective: The aim of this study is to describe the initial antibiotic treatment regimens, severity of illness, and in-hospital mortality among culture-negative (CN) and culture-positive (CP) patients with health-care-associated pneumonia (HCAP)., Methods: We used a retrospective cohort study, examining adult patients with HCAP from Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital., Results: Eight hundred seventy patients with HCAP were identified over a 3-year period (January 2003 through December 2005) of whom 431 (49.5%) were CP. Among the non-CP patients, 290 (66.1%) had no respiratory cultures obtained, and 149 (33.9%) had no growth or nonpathogenic oral flora identified and were classified as CN. CN patients were more likely to have received an initial antibiotic regimen (ceftriaxone +/- azithromycin or moxifloxacin) targeting community-acquired pneumonia pathogens compared with CP patients (71.8% vs 25.5%, P < .001). Severity of illness as assessed by ICU admission and mechanical ventilation (MV) was statistically lower in CN compared with CP patients (ICU admittance 12.1% vs 48.7%, P < .001; MV: 6.7% vs 44.5%, P < .001). In-hospital mortality and hospital length of stay were also statistically lower for CN patients (mortality: 7.4% vs 24.6%, P < .001; hospital length of stay: 6.7 +/- 7.4 days vs 12.1 +/- 11.7 days, P < .001)., Conclusions: In this analysis, patients with CN HCAP had lower severity of illness, hospital mortality, and hospital length of stay compared with CP patients. These data suggest that patients with CN HCAP differ substantially from patients with HCAP with positive microbiologic cultures.