AIM: To investigate the relationship between gallbladder stone disease (GSD) and single nucleotide polymorphisms of cholesterol 7α-hydroxylase (CYP7A) gene promoter,apolipoprotein (4PO) B gene exon 26, 4POEgene exon 4 or microsatellite polymorphism of low density lipoprotein receptor (LDLR) gene exon 18.METHODS: Genotypes of CYP7A, APOB, APOE and LDLR genes were determined in 105 patients with GSD diagnosed by B-mode ultrasonography and 274 control subjects.Serum lipids were analyzed with HITACHI 7060 automaiC biochemical analyzer.RESULTS: Body mass index (BMI) was significantly higher in patients with GSD (24.47±3.09) than in controls (23.50±2.16).Plasma total cholesterol was lower in patients with GSD (4.66±0.92 mmol/L) than in controls (4.91±0.96 mmol/L),P＜0.01 after adjusted for age, sex and BMI. The significantly higher frequency of A allele of CYP7,4 gene polymorphism and X+ allele of APOBgene polymorphism was seen in GSD patients. Percentages of A allele in patients and controls were 62.86% and 54.38% (P ＜0.05) and those of X+ allele 8.57% and 4.01% (P＜0.01). Subjects with A allele had significantly lower plasma total cholesterol and LDL cholesterol than subjects with CC homozygote. In a multiple variable logistic regression model, the BMI (OR=1.13, 95% CI: 1.05-1.22), A allele (OR=1.48, 95% CI: 1.05-2.09) and X+ allele (OR=2.28, 95% CI: 1.14-4.59) were positively associated with GSD (P ＜0.05). Plasma total cholesterol (OR=0.69, 95% CI: 0.64-0.74) was negatively related to SSD (P＜0.05).CONCLUSION: With an association analysis, it was determined that A allele of CYP74 gene and X+ allele of 4POBgene might be considered as risk genes for GSD. These alleles are related with differences of serum lipids among subjects.Multiple-variable logistic regression model analysis showed that besides BMI, GSD was affected by polygenetic factors.But the mechanism for these two alleles responsible for GSD requires further investigations.