background: ADAM9, 10, and 17 are a class of disintegrins and metallproteinases with α-secretase activity. There are conflicting results regarding the role(s) of ADAM9, 10, and 17 in carcinogenesis, and only a few studies have examined their levels and cellular localization in renal cell carcinoma (RCC). Studies examining changes in α-secretase activity in RCC compared to enzymatic activity of the uninvolved kidney are lacking. method: A cross-sectional study was conducted in 56 patients undergoing radical nephrectomy after the diagnosis of RCC. α-Secretase activity was determined using flourogenic substrate in freshly frozen tumor tissues as well as similarly treated tissues from the neighboring kidney. Immunohistochemical analyses of ADAM9, 10, and 17 were also performed. results: α-Secretase activity decreased markedly in all types of RCC as compared to neighboring uninvolved kidney tissue having 5 to 10 times higher levels of α-secretase activity. Although type-dependent variations were observed, tumoral expressions of ADAMs, except for ADAM17, were lower in the tumors compared to that of neighboring tissues, but the changes in α-secretase activity were greater. In RCC tissue, ADAM9 expressions were localized in nuclear and cytoplasmic compartments, whereas ADAM10 and 17 were present predominately in the cytoplasm potentially explaining the markedly decreased enzyme activity. Membranous localization of ADAMs was noted in uninvolved kidney tissue. conclusions: The loss of α-secretase activity observed here in conjunction with previous findings argue against tumorigenic effects of ADAM9, 10, and 17 supporting that increased nuclear and cytoplasmic expression may be an attempt to compensate for loss of function.