Primary prophylaxis with antifungal interventions may decrease cryptococcal disease incidence and associated mortality.<br><b>OBJECTIVES</b>: To assess the efficacy of antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV.<br><b>SEARCH STRATEGY</b>: We searched the following databases: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), Latin American and Caribbean Literature on the Health Sciences (LILACS), and the Cochrane Controlled Trials Register (CCTR).