A 22-year-old black man was hospitalized with fever, rash, myalgias, and marked periorbital and facial edema three months after beginning phenytoin therapy. His hospital course was marked by an initial serum creatine phosphokinase level of 85,000 IU/liter, which rose to a peak value of 242,000 IU/liter on the third hospital day and a striking eosinophilia (8,400/microliter). Muscle biopsy revealed only early fiber necrosis with partial dissolution of the sarcoplasm without evidence of inflammation, vasculitis, regeneration, or parasitic infection. When therapy with phenobarbital, a structural congener of phenytoin, was begun, the patient had an exacerbation of his rash and became febrile again.