BackgroundArteriosclerosis in multiple arteries has long been associated with heightened cardiovascular risk. Acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) play an important role in the pathogenesis of arteriosclerosis by participating in the oxidation and reduction reactions in vascular endothelial cells. The purpose was to investigate the relationship ofALDH2andMTHFRgene polymorphisms with arteriosclerosis in multiple arteries.Methods410 patients with arteriosclerosis in single artery and 472 patients with arteriosclerosis in multiple arteries were included. The relationship betweenALDH2rs671 andMTHFRrs1801133 polymorphisms and arteriosclerosis in single artery and arteriosclerosis in multiple arteries was analyzed.ResultsThe proportion ofALDH2rs671 A allele (35.6% vs. 30.9%,P= 0.038) andMTHFRrs1801133 T allele (32.6% vs. 27.1%,P= 0.012) in patients with arteriosclerosis in multiple arteries was significantly higher than that in arteriosclerosis in single artery, respectively. The proportion of history of alcohol consumption in patients withALDH2rs671 G/G genotype was higher than those inALDH2rs671 G/A genotype and A/A genotype (P< 0.001). The results of logistic regression analysis indicated thatALDH2rs671 A/A genotype (A/A vs. G/G: OR 1.996, 95% CI: 1.258–3.166,P= 0.003) andMTHFRrs1801133 T/T genotype (T/T vs. C/C: OR 1.943, 95% CI: 1.179–3.203,P= 0.009) may be independent risk factors for arteriosclerosis in multiple arteries (adjusted for age, sex, smoking, drinking, hypertension, and diabetes).ConclusionsALDH2rs671 A/A andMTHFRrs1801133 T/T genotypes may be independent risk factors for arteriosclerosis in multiple arteries.