A case of severe, oral, not otherwise specified ulcers in a human immunodeficiency virus-infected patient is described. The lesions did not respond to acyclovir, prednisone, pentoxifylline, or foscarnet sodium therapy. Dramatic clinical improvement and progressive ulcer healing were observed after starting oral thalidomide therapy. Clinicians should be aware of the usefulness of thalidomide for the treatment of acquired immunodeficiency syndrome-associated not otherwise specified ulcerations.