Helicobacter pylori (H. pylori) infection is associated with an increased risk of gastrointestinal (GI) cancers, but its impact on immunotherapy for GI cancers remains unclear. This study included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer (GC) treated with anti-PD-1/PD-L1 therapy, H. pylori–positive patients exhibited significantly longer immune-related progression-free survival (irPFS) and median immune-related overall survival (irOS) compared to H. pylori–negative patients. H. pylori–positive GC displayed a "hot" tumor microenvironment with higher densities of PD-L1+ cells and nonexhausted CD8+ T cells. Transcriptomic analysis revealed that H. pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori–positive patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS and irOS compared to H. pylori–negative patients. The study highlights the importance of testing for H. pylori infection in cancer patients treated with immunotherapy, as it can influence the efficacy of immunotherapy in different types of GI cancers.Helicobacter pylori (H. pylori) infection is associated with an increased risk of gastrointestinal (GI) cancers, but its impact on immunotherapy for GI cancers remains unclear. This study included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer (GC) treated with anti-PD-1/PD-L1 therapy, H. pylori–positive patients exhibited significantly longer immune-related progression-free survival (irPFS) and median immune-related overall survival (irOS) compared to H. pylori–negative patients. H. pylori–positive GC displayed a "hot" tumor microenvironment with higher densities of PD-L1+ cells and nonexhausted CD8+ T cells. Transcriptomic analysis revealed that H. pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori–positive patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS and irOS compared to H. pylori–negative patients. The study highlights the importance of testing for H. pylori infection in cancer patients treated with immunotherapy, as it can influence the efficacy of immunotherapy in different types of GI cancers.