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Peroxisome proliferator-activated receptor gamma (PPARγ) is involved in obesity and in some components of the metabolic syndrome in unselected population. To determine whether PPARγ genetic variants are associated with the risk of developing lipodystrophy and its associated metabolic disturbances in HIV-1-infected patients treated with HAART and to assess PPARγ mRNA expression in subcutaneous adipose tissue (SAT). The study group comprised 278 patients infected with HIV-1 and treated with antiretroviral drugs (139 with lipodystrophy and 139 without) and 105 uninfected controls (UC). The PPARγ Pro12Ala (C>G) single nucleotide polymorphism (SNP) was assessed using PCR-RFLPs on white cell DNA. PPARγ mRNA expression in SAT was assessed in 38 patients (25 with lipodystrophy and 13 without) and in 21 UC by real-time PCR. Statistical analysis was based on Student's T tests, χ2 tests, Spearman's correlations tests and logistic regression tests. PPARγ Pro12Ala genotype distribution and allele frequencies were non-significantly different between both HIV-1-infected categories, lipodystrophy vs non-lipodystrophy (p = 0.9 and p = 0.87, respectively). Lipodystrophic patients harbouring the rare X/Ala genotype (Ala/Ala plus Pro/Ala) had significantly greater plasma total and LDL cholesterol levels compared with carriers of the common Pro/Pro genotype (p = 0.029 and p = 0.016, respectively) at univariate analyses. At multivariate analyses these associations were no longer significant. There was a near-significant decreased SAT PPARγ mRNA expression in patients with lipodystrophy compared to UC (p = 0.054). PPARγ Pro12Ala SNP has no effect on the risk of developing lipodystrophy in HIV-1-infected patients treated with HAART. PPARγ mRNA SAT expression appears decreased in lipodystrophy.