Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. This study is the longest prospective cohort of an H. pylori eradication trial in a Hispanic population.800 adults with precancerous lesions were randomized to anti-H. pylori treatment or placebo. Gastric biopsies at baseline, 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a subject level random intercept was used to estimate the effect of H. pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis, and GC risk by intestinal metaplasia (IM) subtype and anatomic location.356 individuals completed 20 years of follow-up. Anti-H. pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio OR, 0.59, 95% confidence interval, CI, 0.38-0.93). H. pylori-negative status had a beneficial effect on the score over time (P=0.036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs. complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs. antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC.In a high GC risk Hispanic population, anti-H. pylori therapy had a long-term beneficial effect against histological progression. Incomplete IM is a strong predictor of GC risk.