AbstractGene–environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile,Helicobacter pylori(H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene–environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions withH. pyloriinfection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications byH. pyloriinfection, smoking and alcohol drinking were evaluated.PSCArs2294008/rs2976392 showed a significant, multiplicative interaction withH. pyloriinfection in risk of GC. Meanwhile,PRKAA1rs13361707 had an additive interaction withH. pyloriinfection.SLC52A3rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs,MUC1rs4072037,ZBTB20rs9841504 andPRKAA1rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly forH. pyloriinfection and alcohol consumption, to increase the risk of GC.