Objective to evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. Design 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. a total of 456 individuals attended the 16-year visit. cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (iM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). the score difference between baseline and 16 years was modelled by generalised linear models. Results individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). incomplete-type iM was associated with higher risk of progression to cancer than complete-type (Or, 11.3; 95% ci 1.4 to 91.4). the average histopathology score increased by 0.20 units/year (95% ci 0.12 to 0.28) among individuals continuously infected with H. pylori. the effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without iM) than for individuals with iM (p<0.001). Conclusions long-term exposure to H. pylori infection was associated with progression of precancerous lesions. individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without iM. incomplete-type iM may be a useful marker for the identification of individuals at higher risk for cancer.