Among patients with HIV/AIDS, mucosal lesions of unknown etiology such as recurrent aphthous ulcerations (RAUs) often are unresponsive to standard therapies, resulting in substantial morbidity. The literature regarding RAUs suggests that the inflammatory response contributes to its pathogenesis; however, the role of cytokines in this mucosal immune response remains largely unknown. Thalidomide first was marketed as a sedative in the 1950s and withdrawn from the market in 1961 following reports of teratogenicity. Later, it was used as an investigational agent for the treatment of Hansen's disease, Kaposi's sarcoma, myelofibrosis, RAUs, and wasting associated with HIV. Thalidomide's mechanism of action in RAUs still is not understood completely, but it appears to be mediated by inhibition of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha). This article discusses the current status of thalidomide for treating RAUs in HIV-positive patients. Suggestions regarding the safe and effective prescribing of thalidomide have been included so that dental professionals will be able to treat these patients safely.