In recent years, thalidomide has been used for the treatment of a variety of ulcerative and immunologic conditions. Several previous reports have suggested that thalidomide therapy is beneficial for patients with aphthous ulceration related to human immunodeficiency virus (HIV) infection. We describe the use of thalidomide in 20 HIV-infected patients with oropharyngeal, esophageal, and rectal ulceration. Nineteen patients had a dramatic response to thalidomide therapy, with both subjective and objective abatement in the signs and symptoms of their ulcerative disease. The standard treatment course was 200 mg of thalidomide for 14 days (the drug was administered at night). Four patients required additional courses of treatment because symptoms recurred after thalidomide therapy was stopped. Side effects due to thalidomide included rash (5 patients), peripheral neuropathy (1 patient), and excessive fatigue (1 patient). There did not appear to be any adverse immunologic effects in thalidomide-treated patients. The mechanism of the effect of thalidomide is uncertain, although recent studies have suggested that thalidomide selectively inhibits the production of tumor necrosis factor alpha.