Severe sepsis is a heterogeneous syndrome in a heterogeneous population. The current scheme of classification does not enable distinction between systemic inflammatory response syndrome, sepsis and severe sepsis on the basis of the underlying biochemical, immunological and abnormal coagulation features. Planning, implementation and assessment of results of intervention studies on severe sepsis thus present enormous challenges. Two such studies were published in the year 2001. The study investigating the drug drotrecogin alfa (activated) was positive in the day-28 mortality endpoint; however, post-hoc analyses have raised controversies regarding the manner in which the study was carried out, the consistency of results presented, and the suggested mechanism of action. On the other hand, the KyberSept study that investigated antithrombin III reported negative results for the day-28 mortality endpoint, despite correct performance of the study. This, however, was not interpreted to mean proof of therapeutic inefficacy of administering antithrombin III and post-hoc analyses raise the suspicion of an undesirable drug interaction between antithrombin III and heparin. Apparently, neither of the sepsis studies meets the criteria which lie at the basis of critical assessment of the success or failure of clinical trials that could more significantly affect clinical treatment decisions.