Interleukin IL-15 (IL-15) has been implicated in the development of coronary artery disease (CAD). The aim of the present study was to evaluate the role of IL-15 gene polymorphisms as susceptibility markers for development of subclinical atherosclerosis (SA) and cardiovascular risk factors in Mexican population. Four IL-15 gene polymorphisms (rs4956403, rs3806798, rs1057972 and rs10833) were analyzed in a group of 397 individuals with SA and 1120 controls. Under different inheritance models adjusted by traditional risk factors, the rs10833 T allele was associated with increased risk of developing SA [OR = 1.42, Pcodom1 = 0.046; OR = 1.48, Pdom = 0.021; OR = 1.43, Padd = 0.014]. Under a dominant model, the rs1057972 polymorphism was associated with central obesity (P = 0.045) and fatty liver (P = 0.021), while the rs10833 polymorphism was associated with metabolic syndrome (P = 0.007) in individuals with SA. The TAC haplotype was significantly associated with a decreased risk of SA. Individuals with rs10833CC genotype exhibited higher levels of IL-15 than individuals with CT + TT genotypes. The results suggest that IL-15 polymorphisms are involved in the risk of developing SA and are associated with metabolic syndrome, central obesity and fatty liver in our study population. The rs10833 polymorphism could be involved in regulating IL-15 production in SA.