IL-18 is a pleiotropic and multifunctional proinflammatory cytokine that is often produced in response to a viral infection. The biological activities of the cytokine are tightly controlled by its natural antagonist, IL-18 binding protein (IL-18BP), as well as by activation of caspase-1, which cleaves the precursor form of IL-18 into its biologically mature form. The cytokine plays an important role in both innate and adaptive antiviral immune responses. Depending upon the context, it can promote TH1, TH2 and TH17 responses. Increased serum concentrations of IL-18 and concomitantly decreased concentrations of its natural antagonist have been described in HIV-infected persons as compared to HIV-seronegative healthy subjects. We discuss in this review article how increased biological activities of IL-18 contribute towards immunopathogenesis of AIDS, HIV-associated lipodystrophy syndrome and related metabolic disturbances. While the advent of potent anti-HIV drugs has significantly enhanced life span of HIV-infected patients, it has also increased the number of these patients suffering from metabolic disorders. The cytokine may prove to be a useful target for therapeutic intervention in these patients.