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A lipodystrophic syndrome and metabolic abnormalities have been observed in HIV-infected patients treated with highly active antiretroviral therapy (HAART). A murine model of lipodystrophy is associated with decreased levels of adiponectin, an adipocyte-secreted protein, the administration of which improves the metabolic syndrome in these mice. To investigate the association of adiponectin with metabolic changes in human lipodystrophy, we conducted a cross-sectional study of 112 HIV-infected patients treated with HAART.Mean adiponectin levels were higher in patients with no fat redistribution (FR) vs. FR (4.8 ± 5.0 vs. 2.2 ± 2.7 μg/ml, P < 0.01), but no significant differences in adiponectin levels were observed between FR subgroups. The difference in adiponectin levels between subjects with and without FR remained significant after adjusting for age, gender, leptin, HIV medication use, and CD4 count using logistic regression (odds ratio, 0.54, P = 0.008). Adiponectin was significantly correlated with triglycerides (r = −0.40), abdominal visceral fat (r = −0.35), extremity fat (r = 0.37), insulin resistance (HOMA-IR) (r = −0.28), nucleoside reverse transcriptase inhibitor (NRTI) use (r = −0.32), and high-density lipoprotein (HDL) (r = 0.41) using bivariate analysis (all P < 0.01). The association with HDL weakened but remained significant on multivariate analysis (standard β = 0.29, P = 0.01). However, the association of adiponectin with HOMA-IR became nonsignificant after adjusting for NRTI use (standard β = −0.15, P = 0.12), suggesting that changes in adiponectin levels may underlie the effect of NRTI use on insulin resistance. The associations of adiponectin with triglycerides and HOMA-IR were also slightly weakened after adjusting for visceral and extremity fat, indicating that adiponectin may, in part, mediate the effect of FR on triglycerides and insulin resistance.This study indicates that adiponectin is inversely correlated with abdominal visceral fat mass, serum triglycerides, and insulin resistance and is directly correlated with HDL and extremity fat in a sample of HIV-infected patients treated with HAART. The results also indicate that NRTI use may worsen insulin resistance by decreasing adiponectin levels. Thus, adiponectin replacement may be a potential treatment option to ameliorate the metabolic changes observed in this patient population.