Warfarin-induced skin necrosis (WISN) and calciphylaxis share similar early clinical findings and can both lead to significant morbidity and mortality. The authors reviewed the literature on both conditions and describe a case of extensive skin necrosis in a patient with end-stage renal disease who was initially suspected to have calciphylaxis. Further investigation supported a diagnosis of WISN. The pathogenesis, clinical manifestations and treatment of WISN and calciphylaxis are discussed, with emphasis on a diagnostic approach for early recognition.