INTRODUCTION: Helicobacter pylori (HP) is a well-established gastric carcinogen. But it shows inconsistent association with colorectal cancer (CRC) across diverse study populations. METHODS: We investigated participants from the UK biobank. HP-seropositive cases and peptic ulcer diseases (PUDs) were identified. The primary outcome was CRC. We estimated the cumulative incidence using a competing risk model measured by the hazard ratios (HRs) with 95% confidence intervals (CIs) with adjustment. We did a genome-wide interaction analysis to identify genetic variants that modify HP-serology-CRC associations with exploratory gene-based and gene-set analysis. We further did a bidirectional two-sample Mendelian randomization (MR) to investigate the causal relation of gene-proxied PUD on CRC of the European ancestry and of the East Asian ancestry. RESULTS: We included 492,490 participants with a median follow-up of 14.7 years. HP sero-positivity did not significantly increase the incidence of CRC (adjusted HR = 0.76, 95% CI 0.53 - 1.10, p = 0.15). No SNP was identified to be significantly interacted with HP serology to modify CRC risk. The risk of CRC for PUD cases was not significantly different from non-PUD cases after adjusting (adjusted HR = 0.88, 95% CI 0.76 - 1.02, p = 0.09). The gene-proxied PUD causally increased the incidence of colon cancer of the East Asian ancestry (OR = 1.47, 95% CI = 1.00 - 2.15, p = 0.047), not of the European ancestry (OR = 1.03, 95% CI = 0.79 - 1.34, p = 0.82). CONCLUSIONS: Neither seropositivity for HP nor PUD showed a robust increase on the risk of CRC in a 15-year follow-up. The causal relation of PUD on CRC was significant of East Asian ancestry, not of European ancestry.