Abstract Background: Although several studies have investigated the association between ABO blood type and risk of gastric cancer (GC), atrophic gastritis (AG), and Helicobacter pylori (HP) infection, no study has investigated these associations by using ABO genotype. Methods: We conducted a case–control study in 703 patients with GC and 1,465 noncancer patients. We also conducted a cross-sectional study by using 1,406 of these 1,465 controls, who were examined for pepsinogens and anti-HP IgG antibody levels in serum. ABO genotype was determined from single nucleotide polymorphisms in ABO gene. We used rs8176719 to mark the O allele, and rs8176746 and rs8176747 to mark the B allele. ORs and 95% CIs were calculated by a multivariate logistic model. Results: We observed significant associations between ABO genotype and GC, AG, and HP infection. ORs (95% CIs) of GC were 0.70 (0.50–0.99) for OO and 0.53 (0.36–0.77) for BO relative to AA genotype. An increased risk of GC was observed with addition of the A allele (Ptrend < 0.001), and a decreased risk with that of the B allele (Ptrend = 0.023). An OR of AG was 0.73 (95% CI, 0.53–0.99) for blood type B relative to blood type A, and an OR of HP infection was 0.39 (95% CI, 0.17–0.87) for BB relative to AA genotype. Conclusion: This study identified a statistically significant association between ABO genotype and GC risk. In addition, ABO gene locus may influence AG prevalence and HP infection. Impact: Further studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 20(8); 1665–72. ©2011 AACR.