Background: Recently, CD40 polymorphism was found to be associated with acute coronary syndromes. However, few study was involved in the relationship between CD40 polymorphism and the risk of the vulnerable plaque to rupture so far. Materials and Methods: A total of 699 patients who have received coronary angiography were divided into 3 groups according to the morphological division of the plaques: complex lesions (343 cases), smooth lesions (131 cases), and control group (225 cases).The gene polymorphism was measured by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and identified by sequencing. Results: The CC genotype and C allele frequency of the CD40 gene in the complex lesions group is significantly higher than in the smooth lesions group and the control group (P < .001), while the TT genotype frequency in the complex lesions group is significantly lower than that of the smooth lesions group and the control group (P < .001). The C allele increased disruption risk of the plaques in the complex lesions group as compared with the smooth lesions group (odds ratio [OR]: 1.697, 95% confidence interval [CI]: 1.273-2.261). No significant differences in genotypes or allele frequencies were found between the smooth lesions group and the control group. Conclusion: Our results suggested that CD40 (−1C/T) polymorphism was associated with unstable coronary atherosclerotic plaques. The C allele frequency increased the risk of disruption of the coronary atherosclerotic plaques.