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Our primary goal was to evaluate the impact on in-hospital mortality rate of adequate empirical antibiotic therapy, after controlling for confounding variables, in a cohort of patients admitted to the intensive care unit (ICU) with sepsis. The impact of adequate empirical antibiotic therapy on early (<3 days), 28-day, and 60-day mortality rates also was assessed. We determined the risk factors for inadequate empirical antibiotic therapy.Prospective cohort study.ICU of a tertiary hospital.All the patients meeting criteria for sepsis at admission to the ICU.None.Four hundred and six patients were included. Microbiological documentation of sepsis was obtained in 67% of the patients. At ICU admission, sepsis was present in 105 patients (25.9%), severe sepsis in 116 (28.6%), and septic shock in 185 (45.6%). By multivariate analysis, predictors of in-hospital mortality were Sepsis-related Organ Failure Assessment (SOFA) score at ICU admission (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.19–1.40), the increase in SOFA score over the first 3 days in the ICU (OR, 1.40; 95% CI, 1.19–1.65), respiratory failure within the first 24 hrs in the ICU (OR, 3.12; 95% CI, 1.54–6.33), and inadequate empirical antimicrobial therapy in patients with “nonsurgical sepsis” (OR, 8.14; 95% CI, 1.98–33.5), whereas adequate empirical antimicrobial therapy in “surgical sepsis” (OR, 0.37; 95% CI, 0.18–0.77) and urologic sepsis (OR, 0.14; 95% CI, 0.05–0.41) was a protective factor. Regarding early mortality (<3 days), factors associated with fatality were immunosuppression (OR, 4.57; 95% CI, 1.69–13.87), chronic cardiac failure (OR, 9.83; 95% CI, 1.98–48.69) renal failure within the first 24 hrs in the unit (OR, 8.63; 95% CI, 3.31–22.46), and respiratory failure within the first 24 hrs in the ICU (OR, 12.35; 95% CI, 4.50–33.85). Fungal infection (OR, 47.32; 95% CI, 5.56–200.97) and previous antibiotic therapy within the last month (OR, 2.23; 95% CI, 1.1–5.45) were independent variables related to administration of inadequate antibiotic therapy.In patients admitted to the ICU for sepsis, the adequacy of initial empirical antimicrobial treatment is crucial in terms of outcome, although early mortality rate was unaffected by the appropriateness of empirical antibiotic therapy.