Human immunodeficiency virus (HIV) infection leads to a state of CD4 lymphopenia and generalized immune activation with subsequent development of opportunistic infections and neoplasms. The use of highly active antiretroviral treatment has dramatically improved the clinical outcome for HIV-infected patients, but the associated cost and toxicity and the eventual development of drug resistance have underscored the need for additional therapeutic strategies. Immune-based therapies, such as treatment with cytokines or immunosuppressants, adoptive immunotherapy, and therapeutic immunizations, are being intensely investigated as potential supplements to antiretroviral therapy. Although much data have been generated as a result of these efforts, to date there has been little evidence of the clinical efficacy of these strategies. Randomized clinical studies remain critical in evaluating the clinical significance and the role of immune-based therapies in the therapeutic armamentarium against HIV.