In this clinical vignette, we present a case of a 59-year-old woman with catastrophic antiphospholipid syndrome likely triggered by polymicrobial sepsis. The diagnostic criteria and clinical manifestations of catastrophic antiphospholipid syndrome are reviewed. We also compare diagnostic criteria and clinical manifestations with other clinical entities in the differential diagnosis, including thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome, disseminated intravascular coagulation, sepsis, and inflammatory bowel disease. Catastrophic antiphospholipid syndrome is a rare, but lethal condition, and treatment recommendations are based on expert consensus and analyses of the international Catastrophic Antiphospholipid Syndrome Registry. Current management guidelines recommend triple therapy, with anticoagulation, glucocorticoids, and plasma exchange or intravenous immunoglobulins. This case brings this rare clinical entity to the attention of clinicians and emphasizes the need for more research to understand the best management. It also raises the question of whether high-dose steroids should be continued for treatment of catastrophic antiphospholipid syndrome in the setting of a severe sepsis.