Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. This study examined whether it is also a risk factor for primary gastric non-Hodgkin's lymphoma. A nested case-control study was conducted in two large cohorts (230,593 participants). Serum samples were collected and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkin's lymphoma were identified, each matched to four controls. For comparison, 31 patients with nongastric non-Hodgkin's lymphoma were evaluated, each matched to two controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples were tested for H. pylori IgG using an enzyme-linked immunosorbent assay. Primary gastric non-Hodgkin's lymphoma is uncommon, accounting for 10% of lymphomas and 3% of gastric neoplasms. Gastric non-Hodgkin's lymphoma remains the most common extranodal form of this lymphoma. Most tumors are diffuse, large-cell lymphomas, and most are of B-cell lineage. Circumstantial evidence suggests that H. pylori infection may increase the risk of gastric non-Hodgkin's lymphoma. Sixty percent of gastric non-Hodgkin's lymphomas evolve from chronic gastritis, usually caused by H. pylori. An unexpected link between H. pylori infection and the development of gastric non-Hodgkin's lymphoma was identified, although the association was not statistically significant. A region in Europe with a high incidence of gastric non-Hodgkin's lymphoma had a higher rate of H. pylori infection than a region with a low incidence. A possible association between H. pylori and non-Hodgkin's lymphoma was also seen in a large multiregion study in China. Results showed that patients with gastric non-Hodgkin's lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95% confidence interval, 2.0 to 19.9). No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95% confidence interval, 0.5 to 3.0). Conclusions: Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. This study examined whether it is also a risk factor for primary gastric non-Hodgkin's lymphoma. A nested case-control study was conducted in two large cohorts (230,593 participants). Serum samples were collected and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkin's lymphoma were identified, each matched to four controls. For comparison, 31 patients with nongastric non-Hodgkin's lymphoma were evaluated, each matched to two controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples were tested for H. pylori IgG using an enzyme-linked immunosorbent assay. Primary gastric non-Hodgkin's lymphoma is uncommon, accounting for 10% of lymphomas and 3% of gastric neoplasms. Gastric non-Hodgkin's lymphoma remains the most common extranodal form of this lymphoma. Most tumors are diffuse, large-cell lymphomas, and most are of B-cell lineage. Circumstantial evidence suggests that H. pylori infection may increase the risk of gastric non-Hodgkin's lymphoma. Sixty percent of gastric non-Hodgkin's lymphomas evolve from chronic gastritis, usually caused by H. pylori. An unexpected link between H. pylori infection and the development of gastric non-Hodgkin's lymphoma was identified, although the association was not statistically significant. A region in Europe with a high incidence of gastric non-Hodgkin's lymphoma had a higher rate of H. pylori infection than a region with a low incidence. A possible association between H. pylori and non-Hodgkin's lymphoma was also seen in a large multiregion study in China. Results showed that patients with gastric non-Hodgkin's lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95% confidence interval, 2.0 to 19.9). No association was found between nongastric non-Hodgkin's lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95% confidence interval, 0.5 to 3.0). Conclusions: Non-Hodgkin's lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.