Envenomation by the brown recluse spider (loxoscelism) is classically associated with a necrotic ulcer. Systemic manifestations occur in a minority of cases, but are generally mild and self-limited. The hematologic complications of brown recluse spider bite range from mild hemolysis to fulminant intravascular hemolysis with or without evidence of disseminated intravascular coagulation. Intravascular hemolysis is a rare but occasionally lethal complication of brown recluse spider envenomation. This article presents two cases of severe hemolysis associated with loxoscelism occurring in two young women in Memphis, Tennessee. The second documented death in an adult from severe hemolysis due to a brown recluse spider bite is reported. A review of the literature emphasizing the pathogenic mechanisms of spider bite hemolysis is also included.