Background Omentin is an adipocytokine with antiinflammatory properties. It has been reported to be involved in atherosclerosis and coronary artery disease. We aimed to investigate the association of omentin Val109Asp polymorphism with coronary artery disease in an Iranian population. Methods For a case-control study, 400 individuals were recruited: 200 with coronary artery disease and 200 healthy controls. Patients with coronary artery disease were diagnosed by angiography as having at least one main coronary artery with more than 50% stenosis. Genotyping of Val109Asp was carried out using a polymerase chain reaction DNA-restriction fragment length polymorphism technique. Results There was no association between Val109Asp polymorphism and the risk of coronary artery disease in our study population ( p = 0.20). However, when subgroup analysis was performed according to sex, there was a significant difference in the distribution of alleles between groups for men ( p = 0.031, odds ratio = 0.57, 95% confidence interval: 0.35–0.95) but not for women ( p = 0.88, odds ratio = 1.03, 95% confidence interval: 0.66–1.61). Conclusions Our results indicate that the Asp allele of Val109Asp (T allele of rs2274907) is more frequent among men with coronary artery disease than healthy men, so it is possibly a risk factor for coronary artery disease in men only. The difference in association between men and women may be due to the different distribution and metabolism of adipose tissue in men and women. More studies with larger sample sizes and in different populations are required to validate our study results.