Helicobacter pylori has been an almost universal constituent of the human microbiome throughout the history of humankind. H. pylori induces a chronic gastric inflammatory response and promotes the development of gastric carcinoma, lymphoma and peptic ulcer disease in a subset of the H. pylori-colonized population. However, its recent disappearance from human populations in the developed world has coincided with the epidemic emergence of allergic asthma, inflammatory bowel disease and some other extra-gastric inflammatory states. Recent animal studies demonstrated that the acquisition of H. pylori infection early in life may reprogram mucosal and systemic immunity in the direction of increased regulatory T cell function and reduced chronic inflammation outside the stomach. We are interested in understanding human immune mechanisms enabling H. pylori to persist long-term in the human stomach while inhibiting inflammation elsewhere. This knowledge may help lead to better understanding of H. pylori’s paradoxical anti-inflammatory role outside the stomach and provide new insights for rational vaccine design against a persistent, but sometimes beneficial, infection.