Objective: To identify the determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment. Design: A retrospective cohort study of hospitalized patients with blood culture positive septic shock (January 2002-December 2007). Setting: Barnes-Jewish Hospital, a 1,250-bed urban teaching hospital. Patients: Four hundred thirty-six consecutive patients with septic shock and a positive blood culture. Interventions: Data abstraction from computerized medical records. Measurements and Main Results: Septic shock was associated with bloodstream infection due to Gram-negative bacteria (59.2%) and Gram-positive bacteria (40.8%). Two hundred twenty-four patients (51.4%) died during their hospitalization. The presence of infection attributed to antibiotic-resistant bacteria was similar for patients who survived and expired (22.6% vs. 20.1%; p = .516). Multivariate logistic regression analysis demonstrated that infection acquired in the intensive care unit (adjusted odds ratio 1.99; 95% confidence interval 1.52-2.60; p = .011) and increasing Acute Physiology and Chronic Health Evaluation II scores (one-point increments) (adjusted odds ratio 1.11; 95% confidence interval 1.09-1.14; p < .001) were independently associated with a greater risk of hospital mortality, whereas infection with methicillin-susceptible Staphylococcus aureus (adjusted odds ratio 0.32; 95% confidence interval 0.20-0.52; p = .017) was independently associated with a lower risk of hospital mortality. Patients infected with methicillin-susceptible Staphylococcus aureus infections were statistically younger and had lower Charlson comorbidity and Acute Physiology and Chronic Health Evaluation II scores compared to patients with non-methicillin- susceptible Staphylococcus aureus infections. Conclusions: Among patients with septic shock who receive appropriate initial antibiotic treatment, acquisition of infection in the intensive care unit and severity of illness appear to be the most important determinants of clinical outcome.