The efficacy of therapy with drotrecogin alfa (activated) (DrotAA) (recombinant human activated protein C) for surgical patients with severe sepsis has been questioned, and there is concern that patients who have undergone surgery recently may be at increased risk of bleeding complications from the drug. This review was performed to analyze recent data and clinical trends in the management of surgical patients with severe sepsis with respect to the efficacy and safety of therapy with DrotAA. Review and synthesis of the pertinent English-language literature. Source control is the mainstay of therapy for surgical infections, including intraabdominal infections, whereas antibiotics, fluid resuscitation, and support of visceral organ function are necessary adjuncts. Therapy with DrotAA can be given to surgical patients, albeit with some delay (most protocols specify a 12-h wait after major surgery to mitigate the perceived increased risk of bleeding), but efficacy as well as safety have been questioned. In the pivotal PROWESS clinical trial, DrotAA therapy did not appear to be efficacious for surgical sepsis, but rigorous scrutiny of surgical indications and adequacy of source control by blinded reappraisal of the PROWESS database suggested that DrotAA therapy may be effective for surgical patients at high risk of death (Acute Physiology and Chronic Health Evaluation [APACHE] II score>or=25 points). Several comparable studies have now been aggregated in the INDEPTH database, which shows a significant reduction in mortality (OR 0.66; 95% CI 0.45-0.97) for therapy with DrotAA of surgical patients with severe sepsis and a high risk of death. The risk of bleeding is higher in surgical patients compared with DrotAA-treated non-surgical patients, but there is a substantial improvement in survival with DrotAA treatment. In contrast, surgical patients at a lower risk of death do not benefit from therapy with DrotAA but are placed at risk for bleeding. Accumulating experience indicates that surgical patients with severe sepsis and a high risk of death (APACHE II>or=25 points) have a significantly lower mortality rate if treated with DrotAA. The increased risk of bleeding associated with therapy is acceptable given the clear improvement in survival. Surgical patients with sepsis who are at lower risk of death do not appear to benefit from therapy with DrotAA, which should be withheld in most circumstances because of the increased risk of bleeding.