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Background: Numerous studies have investigated the relationship between apolipoprotein (Apo) E gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta- analysis aims to comprehensively evaluate the influence of a common e2/e3/e4 polymorphism in Apo E gene on the risk of gallbladder stone disease. Method: Data were analyzed using the RevMan software (V5.1) and a random-effects model was applied irrespective of between-study heterogeneity. Publication bias was weighed using the fail-safe number. Results: There were 17 study populations totaling 1773 cases and 2751 controls for ε2/ε3/ε4 polymorphism of Apo E gene. Overall comparison of alleles ε2 with ε3 in all study populations yielded a 16% decreased risk for GSD (95% confidence interval [95% CI]: 0.68-1.05; P = 0.31; I² = 13%), and comparison of alleles ε4 with ε3 yielded a 25% increased risk (95% confidence interval [95% CI]: 0.97-1.61; P = 0.0003; I² = 63%). Subgroup analysis by study design indicated that the magnitude of association in hospital-based studies was largely significantly strengthened for e4 allelic model (odds ratio [OR] = 1.46; 95% CI: 1.05-2.02; p = 0.0007; I² = 65%). Subgroup analysis by age of controls indicated a remarkably significant elevation in the magnitude of association in age .50 subgroups in e4 allelic model (OR = 1.50; 95% CI: 1.03-2.19; p = 0.0009; I² = 72%). Moreover, subgroup analysis by cases gender indicated a reduction in the magnitude of association in male,30% studies for E2/2 genotypic model (OR = 0.32; 95% CI: 0.07-1.49; p = 0.16; I² = 45%). Conclusions: Our results reveal that Apo E gene e4 allele is a risk factor of gallbladder stone disease, especially in elder people and Chinese population. [ABSTRACT FROM AUTHOR]