The current antiretroviral therapy has improved the clinical outcome of HIV-infected patients. However, the drug toxicity, the emergence of drug-resistant HIV variants and the incomplete reconstitution of immune responses underline the need for additional therapeutic strategies, such as cytokine-based therapy. Interleukin-15 (IL-15) has a central role in the immune response during HIV infection. Recently, defective production of IL-15 has been found in AIDS patients and it might account for the impairment of natural and adaptive immune responses against HIV. IL-15 is more potent than IL-2 and IL-7 in enhancing the function of HIV-specific CD8⁺ T cells and it is a superior HIV vaccine molecular adjuvant. In this Opinion, we propose that IL-15 could be used for clinical intervention in HIV infection.