Historically, clinical trials evaluating treatment of patients with severe sepsis have failed to show a reduction of mortality. However, retrospective analyses of some of these trials showed benefits in certain patient subgroups. Conversely, the recent Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated the safety and efficacy of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a recombinant form of human activated protein C, in adult patients with severe sepsis, is notable in that it is the first trial to show a reduction in 28-day all-cause mortality in the intent-to-treat population compared with the placebo group. When assessing a new intervention, patient exclusion criteria are important considerations in evaluating the evidence from a controlled clinical trial. Appropriate patient selection will be a key factor in the use of this newly approved therapeutic agent to treat severe sepsis. A review of the exclusion criteria used in the PROWESS trial should provide clinicians with a way of differentiating those patients in the critical care setting who will benefit most from treatment with drotrecogin alfa (activated) from those who should not be treated. © 2002 Excerpta Medica, Inc. All rights reserved.