Omentin-1 protein has protective effects against coronary artery disease (CAD). The Val109Asp polymorphism (rs2274907) in the Omentin-1 gene has been associated with CAD risk, but this relationship has not been investigated in patients with type 2 diabetes mellitus (T2DM). To investigate the association between the Omentin-1 Val109Asp polymorphism and CAD risk in Han Chinese patients with T2DM. This case-control study enrolled 465 Han Chinese patients with T2DM from July 2008 to September 2015. Participants were classified as CAD-positive (coronary stenosis > 50% in at least 1 major vessel, n = 249) or CAD-negative (n = 216). The Val109Asp polymorphism was genotyped using PCR-RFLP. Logistic regression analysis was performed to assess the association between genotypes and CAD risk, with adjustment for potential confounders including age, sex, smoking status, hypertension, dyslipidemia, diabetes duration, body mass index, and fasting glucose. The A allele frequency was higher in CAD patients than in controls (34.5% vs 27.5%; OR = 1.386; P = .026). Under the dominant model, TA/AA carriers had increased CAD risk compared with TT homozygotes (adjusted OR = 1.509, 95% CI: 1.025-2.222; P = .037). Stratified analyses showed that smokers carrying the A allele exhibited further elevated CAD risk (adjusted OR = 1.82, 95% CI: 1.02-3.27). The Omentin-1 Val109Asp polymorphism is associated with increased CAD risk in Han Chinese patients with T2DM under the dominant genetic model. Stratified findings suggest that smoking may further heighten CAD susceptibility among A-allele carriers. Integrating genetic and lifestyle factors may improve cardiovascular risk assessment in this population.