Dyslipidemia is common in patients with HIV infection. In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride >250 mg/dl and HDL <45mg/dl; n = 12), HIV-infected men without dyslipidemia (HIV w/o DL; n = 12), and healthy men ( n = 6). Basal rates of glucose production (glucose Ra), glucose disposal (glucose Rd), and lipolysis (palmitate Ra) were similar between groups. The relative suppression of glucose Ra(63 ± 4, 77 ± 2, and 78 ± 3%, P = 0.008) and palmitate Ra(49 ± 4, 63 ± 3, and 68 ± 3%, P = 0.005) during low-dose insulin infusion (plasma insulin ∼30 μU/ml), and the relative stimulation of glucose Rd(214 ± 21, 390 ± 25, and 393 ± 46%, P = 0.001) during high-dose insulin infusion (plasma insulin ∼75 μU/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose Racorrelated with plasma adiponectin ( r = 0.44, P = 0.02) and inversely with plasma IL-6 ( r = −0.49, P < 0.001). Stimulation of glucose Rdcorrelated directly with adiponectin ( r = 0.48, P < 0.01) and inversely with IL-6 ( r = −0.49, P = 0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action.