INTRODUCTION: Helicobacter pylori colonizes the human stomach. Infection causes chronic gastritis and increases the risk of gastroduodenal ulcer and gastric cancer. Its chronic colonization in the stomach triggers aberrant epithelial and inflammatory signals that are also associated with systemic alterations. METHODS: Using a PheWAS analysis in more than 8,000 participants in the community-based UK Biobank, we explored the association of H. pylori positivity with gastric and extragastric disease and mortality in a European country. RESULTS: Along with well-established gastric diseases, we dominantly found overrepresented cardiovascular, respiratory, and metabolic disorders. Using multivariate analysis, the overall mortality of H. pylori–positive participants was not altered, while the respiratory and Coronovirus 2019–associated mortality increased. Lipidomic analysis for H. pylori–positive participants revealed a dyslipidemic profile with reduced high-density lipoprotein cholesterol and omega-3 fatty acids, which may represent a causative link between infection, systemic inflammation, and disease. DISCUSSION: Our study of H. pylori positivity demonstrates that it plays an organ- and disease entity–specific role in the development of human disease and highlights the importance of further research into the systemic effects of H. pylori infection.