The level of interleukin-18 (IL-18) is elevated in patients with HIV infection as well as in people with insulin resistance (IR). As HIV-associated lipodystrophy (LD) shares metabolic characteristics with the metabolic syndrome, it was hypothesized that IL-18 would be elevated in patients with LD. Two groups of HIV-infected men with LD, one with fat accumulation (mixed group) (n = 12) and one without fat accumulation (lipoatrophic group) (n = 15) were included. Controls were HIV-positive men without LD (n = 15) and HIV-negative, age-matched men (n = 12). The levels of plasma IL-18 were elevated in all 3 HIV groups compared with HIV-negative controls (P <0.01). In the HIV groups the lipoatrophic group had the highest IL-18, followed by the mixed group and the HIV-positive controls. Only the differences between the lipoatrophic group and the HIV-positive controls were significant (P <0.01). Plasma IL-18 correlated with tumor necrosis factor-alpha (P <0.05), but not IL-6, adiponectin, or HOMA-IR (homeostasis model of insulin resistance). In contrast to the HIV-negative controls, IL-18 did not correlate with total or low-density cholesterol in either of the HIV groups. An inverse correlation was observed between IL-18 and limb fat (P <0.05). In conclusion, the level of IL-18 is elevated in patients with LD and closely linked to limb atrophy, whereas it is not associated with cholesterol or IR.