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Idiopathic pure sudomotor failure (IPSF) is a rare disease characterized by acquired impairment in total body sweating despite exposure to heat or exercise. Its etiology is unknown but thought to involve defective cholinergic receptors on eccrine sweat glands. This article reviews the epidemiology, pathophysiology, presentation, and management of IPSF. Additionally, we report two cases of IPSF treated with multimodal therapy, including stacked antihistamine regimens and omalizumab, resulting in symptom improvement. This is the first report of treatment of IPSF with omalizumab, although its benefit is uncertain and requires further study., (© 2020 Published by Elsevier Inc. on behalf of Women's Dermatologic Society.)