Objective: To evaluate the effect of iatrogenic menopause on the physiology of the vagina of the ewe, and to evaluate if vaginal changes in ewes can be translated to women with the genitourinary syndrome of menopause (GSM). Design: Animal study, randomised design for ovariectomy or control, blinded for allocation and outcome assessment. Setting: University of Cape Town, South Africa. Population or Sample: Twenty-five Dohne Merino ewes. Methods: Iatrogenic menopause was induced in 20 animals by bilateral ovariectomy. Five animals served as a control group (no intervention). Differences between groups were determined by linear regression analyses (adjusted for baseline scores) at 5 months after ovariectomy. Main Outcome Measures: Vaginal epithelial thickness, pH, vaginal maturation value, vaginal maturation index, epithelial glycogen accumulation, content of elastin fibres, collagen, and vascularity. Results: Ovariectomised ewes showed epithelial thinning of the vaginal wall from 146 µm to 47 µm (mean, p <0.001 ). In addition, epithelial glycogen accumulation (43%) and the vascularity (23%) of the vaginal wall significantly decreased as compared to the control group. No differences were found for vaginal pH, vaginal cytology outcomes, elastin fibres and collagen content. Conclusions: This study established the ewe as a suitable large animal model for GSM. Furthermore, the similar relevant outcomes in humans and ewes hold great value for future translational research for the evaluation and optimisation of different treatment modalities for GSM. Funding: None. Keywords: Atrophy, ewe, genitourinary syndrome of menopause, model, ovariectomy.