Context. - The separation of chromophobe renal cell carcinoma, oncocytoma, and clear cell renal cell carcinoma using light microscopy remains problematic in some cases. Objective. - To determine a practical immunohistochemical panel for the differential diagnosis of chromophobe carcinoma. Design. - Vimentin, glutathione S-transferase alpha (GST-alpha), CD10, CD117, cytokeratin (CK) 7, and epithelial cell adhesion molecule ( EpCAM) were investigated in 22 cases of chromophobe carcinoma, 17 cases of oncocytoma, and 45 cases of clear cell carcinoma. Results. - Vimentin and GST-alpha expression were exclusively observed in clear cell carcinoma. CD10 staining was more frequently detected in clear cell carcinoma (91%) than in chromophobe carcinoma (45%) and oncocytoma (29%). CD117 was strongly expressed in chromophobe carcinoma (82%) and oncocytoma (100%), whereas none of the cases of clear cell carcinomas were immunoreactive. Cytokeratin 7 was positive in 18 (86%) of 22 cases of chromophobe carcinoma, whereas all oncocytomas were negative for CK7. EpCAM protein was expressed in all 22 cases of chromophobe carcinoma in more than 90% of cells, whereas all EpCAM-positive oncocytomas (5/17; 29%) displayed positivity in single cells or small cell clusters. Conclusions. - Using the combination of 3 markers ( vimentin, GST-alpha, and EpCAM), we achieved 100% sensitivity and 100% specificity for the differential diagnosis of chromophobe carcinoma, oncocytoma, and clear cell carcinoma. The pattern of "vimentin(-)/GST-alpha'' effectively excluded clear cell carcinoma, and homogeneous EpCAM expression confirmed the diagnosis of chromophobe carcinoma rather than oncocytoma. CD117 and CK7 were also useful markers and could be used as second-line markers for the differential diagnosis, with high specificity ( 100%) and high sensitivity ( 90% and 86%, respectively).