Abstract Background: Despite experimental evidence showing chemopreventive effects of coffee-related compounds on gastric carcinogenesis, epidemiologic studies generally do not support coffee–gastric cancer associations. Observational data are lacking among high-risk populations with sufficient regular coffee consumption. Methods: We examined the association between caffeinated coffee intake and gastric cancer risk in a population-based cohort that enrolled 63,257 Chinese men and women ages 45 to 74 years between 1993 and 1998 in Singapore. Incident gastric cancer cases (n = 647) were identified after a mean follow-up of 14.7 years. Biomarkers of Helicobacter pylori (H. pylori) infection were measured in a subset of gastric cancer cases with blood collected before cancer diagnosis and their matched controls. Results: In the total cohort, daily versus nondaily coffee intake was associated with a statistically nonsignificant decrease in gastric cancer risk [HR = 0.85; 95% confidence interval (CI), 0.69–1.04]. In women, the inverse association strengthened and reached statistical significance (HR = 0.63; 95% CI, 0.46–0.87). In analyses restricted to never smokers and nondrinkers of alcohol, inverse associations strengthened in the total cohort (HR = 0.69; 95% CI, 0.52–0.91) and in women (HR = 0.52; 95% CI, 0.37–0.74). There was no coffee–gastric cancer risk association among men, regardless of smoking status or alcohol consumption. Similar results were observed in the nested case–control study after adjustment for H. pylori infection. Conclusion: Daily coffee consumption may reduce the risk of gastric cancer in high-risk populations, especially among women. Impact: Research aimed at identifying the compounds in coffee that may protect against gastric carcinogenesis is warranted. Cancer Epidemiol Biomarkers Prev; 23(4); 638–47. ©2014 AACR.