A 52-year-old man with no previous drug allergies or skin disorders developed a widespread papulovesicular rash while receiving an antimicrobial regimen of piperacillin-tazobactam, tobramycin, and vancomycin. Skin biopsy suggested leukocytoclastic vasculitis, which responded well to antibiotic discontinuation and steroid therapy. Fifteen days later, during steroid tapering, an additional course of vancomycin was begun for suspected line infection. The subsequent maculopapular rash that developed was diagnosed as toxic epidermal necrolysis (TEN) based on a second skin biopsy and clinical presentation. This case is consistent with previous reports of vancomycin-associated TEN. Any patient who develops TEN while receiving vancomycin therapy should be evaluated for possible vancomycin-induced TEN.