The natural course of Helicobacter pylori (H. pylori) is poorly understood, as most research in the field has been on patient populations. We studied the natural course of H. pylori and its associations to morphological changes of the gastric mucosa, peptic ulcer, and reflux oesophagitis in a prospective cohort study of subjects with and without dyspepsia. A total of 361 adults (201 men/160 women, mean age 41/42 years) in Sørreisa municipality, Norway who in 1987 were subjected to upper endoscopy and assessed for gastrointestinal symptoms and H. pylori status were followed up in 2004. H. pylori was strongly associated with neutrophilic (odds ratio [OR] 23.79; 95% confidence interval [CI] 11.64:48.61) and mononuclear infiltration (OR 9.43; CI 5.12:17.36), moderately with atrophy of the antrum (OR 1.98; CI 1.17:3.34), but not with atrophy of the gastric body or intestinal metaplasia. Elimination of H. pylori was associated with regression of gastric inflammation and atrophy, whereas intestinal metaplasia progressed. H. pylori was positively associated with peptic ulcer (OR 2.69; CI 1.2:6.02) but not significantly negatively associated with oesophagitis (OR 0.62; CI 0.35:1.09). This is the first prospective study including endoscopic findings of subjects without dyspepsia, to show that the impact of H. pylori on gastric atrophy is only modest, and that eliminating H. pylori does not cause regression of intestinal metaplasia. However, inflammation of the gastric mucosa regresses after H. pylori elimination. H. pylori is only a moderate risk factor for peptic ulcer, and other explanatory factors deserve more attention.