Cytokines play important roles in the pathogenesis of lipodystrophy syndrome (LS). Single nucleotide polymorphisms (SNPs) at positions −607(C/A) and −137(C/G) in the promoter region of the interleukin-18 (IL-18) gene and at position +874(T/A) of the interferon-gamma (IFN-γ) gene are related to the expression of these cytokines. To examine whether IL-18 and IFN-γ polymorphisms are associated with LS, these SNPs were genotyped in 88 human immunodeficiency virus (HIV)-infected patients presenting LS, 79 HIV-infected without LS, and 133 healthy controls. The −607A allele, −607AA genotype, and −137G/–607A and −137C/–607A haplotypes in the IL-18 gene were over-represented in HIV patients presenting LS. The −137G/−607C haplotype was associated with protection against LS. These results indicate that the −607(C/A) SNP is associated with LS development in HIV-infected patients.