BACKGROUND: We recently discovered the spiny mouse (Acomys cahirinus) has a menstrual cycle; the first report of a rodent undergoing natural menstruation1. Use of spiny mice as appropriate models for human menstruation requires a comprehensive understanding of endometrial breakdown, repair and immune responses. AIM: To describe the morphological changes to the endometrial stroma, epithelium and neutrophil recruitment during menstruation in the spiny mouse and compare these to women and the induced mouse model (MoMM)2. METHODS: We collected reproductive tracts of spiny mice during each stage of the menstrual cycle (n=5/group) and subjected tissues to Mallory’s Trichrome for morphological assessment. We performed immunohistochemistry for cytokeratin, to detect epithelial cells, and neutrophil gelatinase lipocalin (NGAL), for neutrophils, in spiny mouse tissues and menstrual endometrium from women and MoMM. RESULTS: Endometrial shedding in the spiny mouse is confined to the stratum functionalis, as in women and MoMM. In all three species, only discrete regions of the uterine horn undergo shedding at any one time. MoMM exhibits extensive induced decidualisation, with transformation of the entire uterine horn. Decidualisation occurs to a lesser degree in both humans and spiny mice, and appears to initiate around the spiral arteries. The spiny mouse more closely resembles human menstrual shedding with focal epithelial breakdown in conjunction with lysis of the underlying stromal extracellular matrix, and unshed stroma of adjacent regions remaining intact beneath cytokeratin positive epithelium. NGAL is localised to the glandular epithelium in human, MoMM and spiny mouse tissues, however overall expression is reduced in the spiny mouse endometrium compared to the human and MoMM. SIGNIFICANCE: The spontaneous decidualisation and patterns of focal endometrial shedding suggests the spiny mouse may provide a more accurate model than the induced mouse model in which to study menstruation and menstrual related disorders in women.