Tamoxifen (TAM) is one of the most used drugs in the prevention and treatment of breast cancer. A set of common side effects was recorded associating its prolonged clinical use that ranges 3–10 years. This study aimed to investigate TAMinduced parietal cells (PCs) injury in rats and the possible protective effect of rhubarb (Rh) water extract (WE). Twentyfour adult female rats were distributed as: control group, TAM-group (3 mg/kg/day TAM for 4-weeks) and TAM+Rhgroup (combined 3 mg/kg/day TAM and 20 mg/kg Rh-WE for 4-weeks). Blood sample before euthanizing rats was tested for vitamin-B12. PCs in stomach fundus were examined using histological and transmission electron microscopic studies, besides immunohistochemistry for Caspase-3, proliferating cell nuclear antigen (PCNA) and hydrogen potassium (H + / K + )-ATPase. Gastric homogenates were inspected for malondialdehyde (MDA) by ELISA. TAM intake induced structural and ultrastructural alteration in rat PCs including ballooning degeneration, apoptosis, decreased canaliculi, increased tubulovesicular system and irregular-shaped mitochondria. A significant increase of Caspase-3 immunostaining and MDA expression in gastric tissue was associated with a significant decrease of PCNA and H + /K + -ATPase-immunostaining and in serum vitamin-B12 as compared to the control group. Combined oral intake of TAM and Rh-WE revealed a significant reversal of the previous findings. Conclusion: Prolonged use of oral TAM substantially affected the structure and function of gastric PCs which can be ameliorated by Rh-WE.