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Loxosceles is an arachnid genus comprising several species in the United States, popularly known as brown recluse spiders. The venom is cytotoxic, complex, and has a mixture of many proteins, some of which function as proteases. Envenomation can cause necrotic skin lesions that may become extensive and take many months to heal. Even more rarely, venom may cause systemic effects, leading to widespread hemolysis, coagulopathy, and death. These symptoms typically occur rapidly within 24-48 hours following the bite. We describe a rare case of a 44-year-old male with fatal systemic loxoscelism with orbital compartment syndrome requiring emergent lateral canthotomy and cantholysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Meadows et al.)