Coccidioidomycosis is an uncommon AIDS-defining illness that is endemic in the southwestern United States. In profoundly immunodeficient patients infected with human immunodeficiency virus (HIV), the disease is usually manifest as severe pulmonary infection and is associated with high mortality. Although diagnosis is often made by routine serological tests, these appear to be less sensitive than when used for patients who are not HIV-infected. New ways to diagnose the infection in HIV-infected patients earlier and with more certainty are urgently needed. The optimal antifungal regimen for active disease in HIV-infected patients is currently undefined, but following acute disease in severely immunocompromised HIV-infected patients (CD4 lymphocyte count, < 200/microL), lifelong systemic antifungal therapy is recommended. The role of chemoprophylaxis for HIV-infected patients in the area of endemic disease is also unclear. Improvement of preventive strategies must await the results of well-designed future studies to determine risk factors, particularly environmental factors, for development of coccidioidomycosis and to determine the proportion of disease due to new vs. reactivated infection. These studies are also needed to elucidate the role and efficacy of different types of antifungal drug therapies and the specific dosages useful for prevention, treatment, and long-term control of these infections.