Recurrent Aphthous Ulceration (RAU) is an inflammatory ulcerative disease of unknown etiology. Although RAU are common in the general population, people with HIV disease may have ulcers that are large and painful and take a long time to heal. Local and systemic steroid therapy has been the traditional method of treatment for recurrent lesions. Recent studies have shown that systemic thalidomide therapy has the best efficacy in the treatment of major RAU in HIV-seropositive patients. Two case histories of complete resolution of the RAU are presented. We have included recommended guidelines for prescribing thalidomide according to the System for Thalidomide Education and Prescribing Safety (STEPS) Program.