This study investigates the association between *Helicobacter pylori* (H. pylori) infection and primary gastric non-Hodgkin's lymphoma (NHL). The research is based on a nested case-control study involving two large cohorts: the Kaiser-Orentreich cohort (128,992 participants) and the Janus cohort (170,000 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 and matched to four controls each, while 31 patients with nongastric non-Hodgkin's lymphoma were evaluated, each matched to two controls. The study found that patients with gastric non-Hodgkin's lymphoma were significantly more likely to have had prior H. pylori infection compared to matched controls (odds ratio, 6.3; 95% confidence interval, 2.0 to 19.9). No such association was found between nongastric non-Hodgkin's lymphoma and prior H. pylori infection (odds ratio, 1.2; 95% confidence interval, 0.5 to 3.0). The odds ratio for prior H. pylori infection was elevated in all subgroups, including those stratified by cohort, sex, age at diagnosis, and the interval between serum collection and diagnosis. The findings suggest that H. pylori infection is specifically linked to lymphomas of gastric tissue, indicating that any detrimental effects of this infection are exerted locally. The study also highlights the importance of individual differences in the inflammatory response to H. pylori infection and the factors influencing this response.This study investigates the association between *Helicobacter pylori* (H. pylori) infection and primary gastric non-Hodgkin's lymphoma (NHL). The research is based on a nested case-control study involving two large cohorts: the Kaiser-Orentreich cohort (128,992 participants) and the Janus cohort (170,000 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 and matched to four controls each, while 31 patients with nongastric non-Hodgkin's lymphoma were evaluated, each matched to two controls. The study found that patients with gastric non-Hodgkin's lymphoma were significantly more likely to have had prior H. pylori infection compared to matched controls (odds ratio, 6.3; 95% confidence interval, 2.0 to 19.9). No such association was found between nongastric non-Hodgkin's lymphoma and prior H. pylori infection (odds ratio, 1.2; 95% confidence interval, 0.5 to 3.0). The odds ratio for prior H. pylori infection was elevated in all subgroups, including those stratified by cohort, sex, age at diagnosis, and the interval between serum collection and diagnosis. The findings suggest that H. pylori infection is specifically linked to lymphomas of gastric tissue, indicating that any detrimental effects of this infection are exerted locally. The study also highlights the importance of individual differences in the inflammatory response to H. pylori infection and the factors influencing this response.