This is the first study from north India that investigated the association of thrombomodulin (TM) polymorphisms with acute myocardial infarction (AMI) in 350 patients (≤ 40 years, n = 184 and ≥ 60 years, n = 166) and 350 matched-controls. The TM polymorphisms were determined by polymerase chain reaction–single-stranded conformational polymorphism and DNA sequencing. The TM 1418TT genotype (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.3-6.4; P = .012) was independent risk predictor of young AMI as were hypertension (OR 3.3; 95% CI 1.8-5.9; P < .001), diabetes mellitus (OR 14.3; 95% CI 2.9-44.6; P = .001), smoking (OR 13.8; 95% CI 7.7-24.7; P < .001), family history (OR 1.8; 95% CI 1.1-3.3; P = .045), high body mass index (OR 2.2; 95% CI 1.3-3.6; P = .002), and high waist–hip ratio (OR 4.1; 95% CI 2.4-7.1; P < .001). Mean plasma TM also showed association with young AMI (P < .001). Smoking carriers of TM 1418CT + TT genotype had significantly higher risk of AMI (OR 12.8; 95% CI 6.0-27.3; P < .001) when compared with nonsmoking noncarriers. In conclusion, TM 1418C/T polymorphism is independent predictor of AMI and synergies with smoking.