Treatment of unsubstantiated Lyme disease has led to serious complications in some cases. Two case-control studies, based on information in clinical records of patients discharged with a diagnosis of Lyme disease during 1990–1992, were conducted at a central New Jersey hospital. Twenty-five patients with biliary disease were identified, and 52 controls were selected from 1352 patients with suspected Lyme disease. Only 3% of 71 evaluatable subjects met the study criteria for disseminated Lyme disease. Patients with biliary disease were more likely than were antibiotic controls to have received ceftriaxone and more likely than ceftriaxone controls to have received a daily ceftriaxone dose ∼40 rug/kg and to be ∼ 18 years old. Fourteen of 25 biliary case-patients underwent cholecystectomy; all had histopathologic evidence of cholecystitis and 12 had gallstones. Thus, treatment of unsubstantiated diagnoses of Lyme disease is associated with biliary complications.