Coronary artery disease (CAD) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. We analyzed whether interleukin-24 (IL-24) gene polymorphisms are associated with premature CAD in a case-control association study. Four polymorphisms (rs1150253, rs1150256, rs1150258, and rs3762344) of the IL-24 gene were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 952 patients with premature CAD, 284 individuals with subclinical atherosclerosis (SA), and 912 controls. The studied polymorphisms were not associated with the risk of premature CAD or SA (P>0.05). Under dominant models adjusted for age, sex, body mass index, and medication, the polymorphisms were associated with cardiometabolic parameters and cardiovascular risk factors. Three polymorphisms (rs1150253, rs1150256, and rs3762344) were associated with hypertension and increased levels of systolic blood pressure in controls. In SA, 2 polymorphisms (rs1150256 and rs3762344) were associated with type 2 diabetes mellitus, gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase, whereas rs1150253 was associated with GGT and type 2 diabetes mellitus and rs1150258 with GGT and alkaline phosphatase. In premature CAD, the 4 polymorphisms were associated with total cholesterol >200 mg/dL, low-density lipoprotein cholesterol (LDL-C), and GGT, whereas rs1150256 was associated also with ApoA. On the other hand, rs1150258 was associated with ApoA, LDL-C >100 mg/dL, and apoB/apoA ratio, and rs3762344 with ApoA, apoB/apoA ratio, LDL-C >100 mg/dL, and total cholesterol. On the basis of single-nucleotide polymorphism functional prediction software, rs1150253 and rs1150258 polymorphisms seem to be functional. The 4 studied polymorphisms were in linkage disequilibrium and had a similar haplotype distribution in patients and controls. Our study demonstrates the association of IL-24 polymorphisms with metabolic and cardiovascular risk factors in individuals with premature CAD, SA, and controls.