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★ A relationship between TNF-α polymorphisms and CAD is proposed. ★ We carried out a case-control study with genotype analysis about TNF-α polymorphisms in Koreans. ★ The G/A polymorphisms at position −238 were significantly associated with CAD. ★ The −238A allele of TNF-α is associated with an increased risk of CAD in Koreans.Coronary artery disease (CAD) results from atherosclerosis, a chronic inflammatory disease mediated in part by proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), which is expressed by atherosclerotic plaques. In this study, we investigated whether TNF-α gene promoter polymorphisms affect the incidence of CAD in Koreans by genotyping. 404 Control subjects and 197 patients who previously received a coronary artery stent for the G/A, C/T, and C/A polymorphisms at position −238, −857 and −863, respectively. The G/G, G/A and A/A genotypes at position −238 occurred in 85.8%, 14.2% and 0% CAD patients and 91.8%, 7.9% and 0.3% control subjects, respectively. The G/A polymorphisms at position −238 were significantly associated with CAD when assuming a dominant model of inheritance (OR = 1.87; 95% CI = 1.10–3.20; P = 0.02), and A allele carriers had a significantly increased risk of developing CAD relative to the G allele (OR = 1.74; 95% CI = 1.04–2.92; P = 0.03). However, the polymorphisms at positions −857 and −863 were not associated with CAD. Haplotype-based analysis revealed the CAD and control groups differed significantly in the frequencies of haplotype ACC at positions −238, −857 and −863 (OR = 1.77; 95% CI = 1.05–2.98; P = 0.03). This was confirmed by multivariate analysis after adjusting body mass index and the presence of diabetes and hypertension (OR = 2.06; 95% CI = 1.15–3.68; P = 0.015). Thus, the −238A allele of TNF-α is associated with an increased risk of CAD and could be used as predictor for CAD in Koreans. Further studies are needed to elucidate the clinical implications of these findings.