Given the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome (SIRS), this study was designed to review the evidence for rhAPC as a possible therapeutic option in the treatment of severe ovarian hyperstimulation syndrome (OHSS). SIRS, like OHSS, is a proinflammatory and prothrombotic disorder whose cornerstone is endothelial dysfunction in which protein C deficiency is a frequent occurrence. Recently, the use of rhAPC has been shown to be of benefit with a reduction in mortality and an improvement in indicators of inflammation and coagulation. OHSS is typically an iatrogenic disorder resulting from ovarian stimulation as a component of infertility treatment. The pathogenesis of OHSS, like sepsis, is related to endothelial dysfunction and inflammation and can result in significant morbidity including end organ hypoperfusion, disseminated intravascular coagulation (DIC), thrombosis, and occasionally, death. We have performed a review of the literature to identify similarities between these disease processes to develop a theoretical basis for the use of rhAPC in patients with moderate to severe OHSS. Use of rhAPC in this group may attenuate the disease process and reduce the potential morbidity associated with this iatrogenic disorder.