AIDS is defined by the occurrence of an opportunistic infection or tumor considered indicative of advanced infection with human immunodeficiency virus (HIV). Even though recent modifications have improved the widely used AIDS case definition issued by the World Health Organization and the Centers for Disease Control and Prevention, the modified version has fallen short of generating a globally functional instrument for the surveillance of HIV-related infections. The clinical AIDS case definition should be as comprehensive as possible. In many countries, only the diagnosis of an AIDS-defining illness will grant the affected patient social benefits or access to medical care. An expanded AIDS case definition is also likely to improve surveillance of HIV-associated morbidity and mortality; increase the awareness of emerging infections; increase the number of clinical endpoints in clinical trials; and facilitate the introduction of diagnostic tests, screening programs, and preventive measures. Examples of opportunistic infections and tumors that could be considered in future modifications of the AIDS case definition are discussed in detail.