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Abstract: Using immunohistochemistry (IHC), this study aimed to evaluate the regional distribution pattern of some biologically active proteins in the epididymis of Egyptian water buffalo and to determine the structural–functional relationships of the different epididymal structures. Wax-embedded sections from different regions of the epididymal duct from adult, clinically healthy, buffalo bulls were used. Primary antibodies against angiotensin converting enzyme (ACE), S-100, galactosyltransferase (GalTase), alpha smooth muscle actin (α-SMA), connexin 43 (Cx43) and vascular endothelial growth factor (VEGF) were used for immunohistochemical studies. The results showed that, in addition to the well-known principal and basal cells, the epididymal epithelium, similar to that of other species, possessed apical cells and intraepithelial leukocytes. IHC showed that, with the exception of VEGF which reacted negatively, all antibodies used displayed variable reactivity in the different epididymal structures. Apical cells expressed a strong reaction with ACE along the entire length of the duct. The principal cells in the caput epididymis exhibited a distinct reactivity with S-100 and GalTase. The peritubular muscular coat displayed a marked immunostaining for α-SMA and for Cx43. In conclusion these findings showed a regional-specific distribution pattern, distinct from that in bovine bulls. Some potential functional capacities, especially absorptive and secretory ones, are discussed in relation to the different epididymal regions. [Copyright &y& Elsevier]