Napsin-A aspartic peptidase (napsin-A) is an aspartic protease that is predominantly expressed in the proximal renal tubules and type II pneumocytes of the lung. Recently, napsin-A was reported to be present in a proportion of renal cell carcinomas (RCCs). However, the utilization of napsin-A immunohistochemistry as a routine diagnostic tool for RCC, and the correlation of the level of napsin-A expression with histologic features have not yet been established. In the current study, using tissue microarrays composed of primary and metastatic RCCs, napsin-A expression was demonstrated in 86 of 222 (39%) clear cell RCCs (CRCCs) and 16 of 21 (76%) papillary RCCs (PRCCs), with a strong and diffuse staining pattern observed in PRCCs and a relatively weak and focal positivity in CRCCs. Compared with primary CRCCs, a comparable proportion of metastatic CRCCs retained napsin-A expression (45/132, 34%), suggesting the potential utility of napsin-A in the evaluation of metastatic tumors. The expression of napsin-A was also found to be inversely correlated to aggressive local tumor characteristics, such as advanced pathologic stage and high Fuhrman nuclear grade. We conclude that napsin-A may be a valuable immunohistochemical marker in the diagnosis of RCCs, particularly PRCC.