Objective:The pathogenic mechanisms underlying lipodystrophy in HIV-positive patients are largely unknown. TNF-α has many actions that are consistent with the features of lipodystrophy; therefore, an analysis was carried out to determine whether functionally active polymorphisms in the promoter region of the TNF-α gene are associated with the development of lipodystrophy.Design:Genetic case–control association study.Methods:Individuals were genotyped for the −238 and −308 polymorphisms in the TNF-α gene using polymerase chain reaction–restriction fragment length polymorphism analysis. The genotype and allele frequencies for 61 HIV-positive patients with lipodystrophy were compared with (a) 35 HIV-positive patients with no evidence of lipodystrophy and (b) 239 healthy HIV-negative individuals.Results:The frequency of the variant rare −238 allele was significantly different (P= 0.01) in HIV-positive patients with lipodystrophy than in those without lipodystrophy. At the genotype level, a trend towards a difference between patients with and without lipodystrophy was observed (χ2for linear trend 5.2,P= 0.02). For the −308 polymorphism, no difference was found in genotype and allele frequencies between HIV patients with and without lipodystrophy.Conclusions:The data suggest that the −238 (but not the −308) promoter region TNF-α gene polymorphism is a determinant in the development of HIV-related lipodystrophy. However, the results need to be confirmed in larger numbers of patients as well as in an ethnically diverse population.