Background/Aim: Long-term acid suppressants are known to have adverse effects. Its effect on gastric mucosa is not known. A cross-sectional study was undertaken to study the effect of Helicobacter pylori on gastric mucosa among patients on longterm acid suppressants. Materials and methods: One hundred and twenty-six patients with symptoms of ulcer type dyspepsia and reflux type dyspepsia for more than a year and on acid suppressants for at least a year were included in the study. Biopsy was obtained from the stomach for demonstration of H. pylori and the histological changes. The duration of treatment and presence of H. pylori was correlated with the histological changes. Results: Sixty-six patients were on omeprazole at a dose of 20 mg a day (group I) and the rest were on ranitidine 150 mg twice a day (group II). Demography and the duration of treatment was comparable in both groups. Gastric mucosa was normal in 18 (27.3%) and 30 (60%) patients in groups I and II respectively, which was statistically significant (p = 0.01). Intestinal metaplasia was significantly more common among those on proton pump inhibitor (PPI) (p = 0.05). None had dysplasia or carcinoma. The colonization of H. pylori correlated with the duration of therapy in each of the two groups but was not statistically significant (p > 0.05). Conclusion: Long-term acid suppressants are generally safe. Gastric mucosal changes especially intestinal metaplasia is more common with PPI with fewer mucosal changes when on H2RA and is not influenced by the presence of H. pylori.