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<p><b>Background</b>: Various single nucleotide polymorphisms (SNPs) have explained the association between<i> Helicobacter pylori</i> (<i>H. pylori)</i> and gastric atrophy and cancer. This study investigated the associations of <i>Grb2 associated binder 1 </i>(<i>Gab1</i>) polymorphism and the combination of <i>PTPN11</i> gene encoding src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP2) and<i> Gab1</i> gene with gastric cancer and gastric atrophy among<i> H. pylori</i> seropositive subjects.</p> <p><b>Methods</b>: A single nucleotide polymorphism at intron 2 of <i>Gab1 </i>(JST164345) was examined for 454 Japanese health checkup examinees (126 males and 328 females) aged 35 to 85 without a history of gastric cancer and 202 gastric cancer patients (134 males and 68 females) aged 33 to 94 with pathologically confirmed diagnosis of gastric adenocarcinoma.</p> <p><b>Results</b>: The decreased OR of the Gab1 A/A for <i>H. pylori </i>seropositivity was 0.25 (95% confidence interval (CI): 0.08-0.71). Among seropositive healthy controls, the OR of the Gab1 G/A+A/A for gastric atrophy was significant (OR=1.95, 95% CI: 1.12 -3.40). Seropositive individuals with PTPN11 G/G and Gab1 G/A+A/A demonstrated the highest risk of gastric atrophy with significance (OR=3.49, 95% CI: 1.54-7.90) relative to PTPN11 G/A+A/A and Gab1 G/G, the lowest risk combination, as a reference. However, the gene-gene interaction between <i>PTPN11 </i>and<i> Gab1 </i>was not observed (OR=1.39, 95% CI: 0.41-4.66). Compared to gastric cancer case, the <i>Gab1 </i>did not influence the step of atrophy/metaplasia-gastric cancer sequence.</p> <p><b>Conclusions</b>: This study represents that the <i>Gab1</i> polymorphism was associated with the low risk of <i>H. pylori </i>infection and the high risk of gastric atrophy among seropositive healthy controls, and that seropositive individuals with PTPN11 G/G and Gab1 G/A+G/G were associated with the greatest risk of gastric atrophy. These findings require confirmation in much larger studies.</p>