Background and Aims: Carbonic anhydrase ΙΧ is ubiquitously expressed during embryogenesis but is downregulated postnatally. CAIX expression persists in the stomach predominantly in the surface cells. We hypothesized that this exoenzyme protects the gastric mucosa against strong luminal acidity. Methods: The cellular differentiation pattern, the acid and bicarbonate secretory capacity, the ability of the surface epithelial cells to withstand a luminal acid load, the mucus layer buildup and the cytokine profiles were assessed in CAIX KO and WT mice from newborn ages to late adulthood. The experiments were performed according to the ethical guidelines that apply for animal experiments. Results: The ability of the surface cells to withstand luminal acid exposure and to generate an alkaline microclimate was significantly impaired in CAΙΧ KO compared to WT stomach. This was accompanied by an increase in IL1ß prior to the gradual expansion of the mucous cell zone and regression of the parietal cell zone to the base of the glands. Maximal acid secretory capacity decreased proportional to the loss of parietal cells and serum gastrin levels increased, explaining the glandular hypertrophy. Mild chronic proton pump inhibition from the time of weaning dramatically reduced the parietal cell loss in CAIX KO mice. Conclusion: We speculate that the CAΙΧ at the basolateral membrane of the gastric surface cells rapidly converts protons extruded by the surface cell basolateral membrane together with blood‑borne HCO3‑ to CO2 and H2O, and thus augments interstitial buffer capacity, surface cell pHi regulation, and maintenance of the pH microclimate in the mucus layer. Lack of CAIX results in chronic acid damage with a gradual regression of the parietal cell zone to the lower gland area.