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Abstract Background The roles of cyclooxygenase - 2 (COX2) −765G > C (rs20417) and −1195G > A (rs689466) polymorphisms in gastric cancer were intensively analyzed, but the results of these studies were inconsistent. We conducted a meta-analysis and trial sequential analysis to elucidate the associations between these two COX2 polymorphisms and gastric cancer risk. Methods Eligible studies were searched in PubMed, Embase, Cochrane library databases, China National Knowledge Infrastructure, Vip, and Wanfang databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the genetic correlation between COX2 polymorphisms and gastric cancer susceptibility in five genetic models. Trial sequential analysis (TSA) was conducted to estimate whether the evidence of the results is sufficient. Furthermore, their interactions with Helicobacter pylori (H. pylori) or smoking in gastric cancer were also assessed using a case-only method. Results The COX2 gene −765G > C polymorphism showed no significant association with gastric cancer susceptibility under all the five genetic models (take the allelic model for example: OR = 1.41, 95% CI: 0.95–2.09) in total analysis, and the stratification analysis by ethnicity indicated a similar association in Caucasian group under four genetic models (allelic model, dominant model, homozygous model, and heterozygous model). But in the subgroup of the Asian population, the −765G > C polymorphism was significantly associated with gastric cancer risk under the same contrast. The COX2 −1195G > A polymorphism showed significant correlation with gastric cancer susceptibility in total analysis, and stratification analysis by ethnicity also revealed a similar association in both Asian and Caucasian groups under the same contrast. Moreover, TSA confirmed such associations. Both H. pylori infection and cigarette smoking interacted with -765 C allele in gastric cancer (OR = 3.79, 95% CI: 1.15–12.43 and OR = 2.48, 95% CI: 1.38–4.48, respectively), but not in −1195 A allele (OR = 1.96, 95% CI: 0.62–6.21, and OR = 1.24, 95% CI: 0.93–1.64, respectively). Conclusions COX2 −765G > C polymorphism may serve as a genetic biomarker of gastric cancer in Asians, but not in Caucasians. COX2 −1195G > A polymorphism may serve as a genetic biomarker of gastric cancer in both Asians and Caucasians. The −765G > C, rather than −1195G > A polymorphism interacted with H. pylori infection or cigarette smoking to increase gastric cancer risk. [ABSTRACT FROM AUTHOR]