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Aquaporin-3 (AQP-3), an aquaglyceroporin, has recently been ascribed a potential role in cell proliferation, migration, and tumorigenesis.The aims of this study was to determine the expression and localization of AQP-3 in normal skin and detect its value in the pathogenesis of nonmelanoma skin cancer such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as well as inflammatory proliferative skin disorders such as psoriasis.The present study comprised a total of 186 samples, including 99 (33 with BCC, 33 with seborrheic keratosis, 3 with SCC, and 30 with plaque psoriasis) patients, 57 (27 SCC and 30 keratoacanthoma) paraffin blocks, and 30 healthy control skin specimens. Biopsies were obtained from the lesional and control skin samples, and examined by hematoxylin and eosin staining and immunohistochemically for AQP-3 expression.There was a statistically significant downregulation of AQP-3 expression between all the cases and control, except in BCC where there was no significant downregulation. BCC had the highest mean value followed by psoriasis, keratoacanthoma, seborrheic keratosis, and finally SCC. Poorly differentiated SCC had the lowest mean value in SCC degrees.The AQP-3 expression was downregulated in the disease groups as compared with normal human skin from the control group, and was decreased in poorly differentiated tumor cells compared with differentiated tumor cells, suggesting that AQP-3 may have a role in the differentiation of these tumors more than proliferation. Therefore, AQP-3 may be considered as an antihyperproliferative prodifferentiative marker.