The prognosis in patients with sepsis depends on severity of acute illness, underlying chronic diseases, and complications associated with infection. Adjusting for these factors is essential for evaluation of new therapies. The purpose of the present study was to determine variables readily identifiable at the bedside that predict mortality in intensive care unit (ICU) patients with sepsis and positive blood cultures. For a 5-yr period, all patients of a surgical ICU presenting with positive blood cultures and sepsis were systematically analyzed for clinical variables and organ dysfunctions at the day of onset of sepsis and bacteremia and during the subsequent clinical course. The prognostic value of these variables was determined using logistic regression procedures. Of the 5,457 admissions to the ICU, 176 patients developed sepsis with positive blood cultures (3.2 per 100 admissions). The fatality rate was 35% at 28 days after the onset of sepsis; in-hospital mortality was 43%. Independent predictors of mortality at onset of sepsis were previous antibiotic therapy (odds ratio [OR], 2.40; 95% confidence interval [CI95], 1.59 to 3.62; p = 0.034), hypothermia (OR, 1.43; CI95, 1.04 to 2.44; p = 0.030), requirement for mechanical ventilation (OR, 2.97; CI95, 1.96 to 4.51; p = 0.009), and onset-of-sepsis APACHE II score (OR, 1.21; CI95, 1.13 to 1.29; p < 0.001). Vital organ dysfunctions developing after the onset of sepsis influenced outcome markedly. The best two independent prognostic factors were the APACHE II score at the onset of sepsis (OR, 1.13 per unit; CI95, 1.08 to 1.17; p = 0.0016) and the number of organ dysfunctions developing thereafter (OR, 2.39; CI95, 2.02 to 2.82; p < 0.001). In ICU patients with sepsis and positive blood cultures, outcome can be predicted by the severity of illness at onset of sepsis and the number of vital organ dysfunctions developing subsequently. These variables are easily assessed at the bedside and should be included in the evaluation of new therapeutic strategies.