Background: Helicobacter pylori is a known risk factor for gastric cancer, possibly via the PD-1/L1 pathway. Some suggest that H. pylori infection may counteract the action of immune checkpoint inhibitors in few studies with limited sample size. This study explores the effects of H. pylori infection status on survival outcomes in patients with gastric cancer. Methods: This single-center, retrospective chart review included patients with gastric adenocarcinoma between June 1985 and August 2022. Patients with different histological subtypes were excluded. Primary variables of interest included H. pylori infection status and treatment with ICIs. Other clinical information included demographics, cancer histology, the presence of other cancers, and vital status. Results: 2,930 patients were included in the initial analysis. 206 (7.0%) received ICIs, 196 (6.7%) had prior H. pylori infection, and 1,037 (35.4%) had a mucinous subtype. Mucinous cancer subtypes were associated with improved survival (p<0.05) at 3 and 5 years compared to non-mucinous adenocarcinomas. Mucinous cancers demonstrated better survival outcomes than non-mucinous at 10 years, but only among H. pylori-positive patients (p=0.013). H. pylori positivity was associated with worse survival at 3 years (OR: 2.0, p=0.041) among patients taking ICIs but not for patients not receiving ICIs (OR: 0.8; p=0.325). Conclusions:H. pylori infection may negatively impact the therapeutic effect of ICIs. These findings suggest H. pylori infection may be an obstacle to successful immunotherapy and may interact with cancer subtypes to differentially impact survival. Future studies are needed to validate the potential prognostic value of H. pylori positivity in gastric cancer.