Objective: This study was designed with the purpose of analyzing the relationship between the interactions of leptin receptor (LEPR) rs1137101, rs1137100 polymorphisms with smoking and the susceptibility to coronary artery disease (CAD). Methods: The subjects of this study consisted of 101 CAD patients and 110 healthy people frequency-matched with the former in age and sex. The genotyping of LEPR polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The distribution differences of genotype and allele between two groups was estimated by chi(2) test. The relative risk of CAD was showed by odds ratio (OR) with 95% confidence interval (95% CI). Crossover analysis was applied in the studying of gene-environment interactions. Results: LEPR rs1137101 polymorphism showed significant difference between CAD patients and healthy controls neither genotypes nor alleles in this study population (P>0.05). Fortunately, we detected that AA genotype of LEPR rs1137100 polymorphism had frequency difference between two study groups with a significant level, compared with the common genotype GG (P=0.03), which showed that this polymorphism had an independent association with CAD (OR=3.07, 95% CI=1.08-8.73). So was A allele of rs1137100 (OR=1.58, 95% CI=1.04-2.39). Furthermore, we observed the interaction of smoking and rs1137100 polymorphism in CAD occurrence (OR=2.69, P=0.01). Conclusions: Not only is LEPR rs1137100 polymorphism an independent risk factor for CAD, but it exists the interaction with smoking in the onset of CAD in this Chinese population.