Thalidomide appears to be highly effective for oropharyngeal apthous ulcers in HIV-infected patients. However, there are limited data regarding the use of this drug for the treatment of HIV-associated idiopathic esophageal ulcer(s) (IEU). Twelve HIV-infected patients with esophageal symptoms and IEU as defined by previously proposed criteria were studied prospectively. Two of these patients had failed oral corticosteroid treatment, and two others had a previous history of IEU. Patients were treated with thalidomide (200 mg/day orally) for 28 days in an open label fashion. Clinical evaluation was performed weekly with endoscopic reexamination performed at the completion of treatment. After therapy, patients were followed clinically with endoscopy recommended for recurrent esophageal symptoms. Of the 12 treated patients, 11 (92%) had a complete symptomatic response; endoscopy in 11 patients at the completion of treatment showed 9 with complete ulcer healing, 1 partially healed, and 1 with no response. All responders were asymptomatic by day 28. The partial responder received an additional 1 month of thalidomide at 300 mg/day, resulting in complete endoscopic healing. The patient failing therapy received prednisone, but died prior to completing this therapy. On follow-up to 20 months, six patients have died with no recurrence of IEU. Three patients had relapse of IEU, two of whom had a prior history of multiple recurrences of IEU; both of these patients relapsed within 2 months of completing thalidomide treatment. The drug was well tolerated without significant side effects. Thalidomide appears to be an effective and well-tolerated alternative to prednisone for the treatment of IEU.