A 17-year-old female patient who had been taking oral minocycline (50 mg twice daily) for 3 weeks for acne developed an eruption that progressed to an exfoliative dermatitis. This illness was also characterized by fever, lymphadenopathy, pharyngitis, a leukemoid reaction, lymphocytosis, eosinophilia, hepatitis, and noncardiogenic pulmonary edema. Dramatic improvement followed institution of corticosteroid therapy. Studies for infectious and collagen vascular diseases were negative. This severe illness was likely caused by minocycline, and we speculate that minocycline may have acted as a superantigen, causing lymphocyte over-activation and massive cytokine release.