Blisters and subsequent desquamation of the skin in the presence of acute edema is a well-known clinical phenomenon. In this case report, we describe a new variant that we have termed anasarca-induced desquamation in a 50-year-old man with molting of the entire cutaneous surface after acute edema, in a setting of 40-lb weight gain over 5 days. Laboratory workup for infectious causes and punch biopsies of skin lesions ruled out Stevens-Johnson syndrome and staphylococcal scalded skin syndrome, which have a similar clinical presentation to anasarca-induced desquamation. In patients with diffuse superficial desquamation in the setting of acute edema, anasarca-induced desquamation is worth investigating to avoid the use of corticosteroids and intravenous antibiotics in this inherently benign condition.