Administration of drotrecogin alfa (activated) has been demonstrated to reduce mortality in patients with severe sepsis who are at high risk for death or who have multiple organ dysfunction. This benefit was associated with an increased incidence of bleeding events, but the latter were mainly procedure related. Drug infusion interruptions should be instituted, in accordance with recent recommendations. Monitoring coagulation parameters may help in identifying patients at higher risk for bleeding but it is not indicated to adjust drug dosage. Acute renal failure and hemodialysis are not contraindications to this therapy, and no drug dosage adjustment is indicated. Finally, the type and source of infection, and its anticipated natural history, may determine whether drotrecogin alfa (activated) is indicated as well as the timing of its administration.