Severe sepsis in immunosuppressed recipients of solid-organ transplants is associated with a high mortality. Conventional management of sepsis in this patient population has not specifically attempted to treat the underlying inflammatory or procoagulant responses that contribute to the development of multisystem organ failure. Drotrecogin alfa (activated, human activated protein C) has been shown to be a safe and effective adjuvant in the treatment of severe sepsis; however, experience in recipients of solid-organ transplants has not been addressed. The treatments and outcomes of three solid-organ transplant recipients (liver, kidney, and kidney-pancreas) who experienced episodes of severe sepsis are presented and demonstrate initial success with the use of drotrecogin alfa (activated).