The variation in cytoplasmic staining and growth pattern makes differential diagnosis of chromophobe renal cell carcinoma (RCC), especially from renal oncocytomas (RO), uncertain. The aim was to find an immunohistochemical marker to improve the diagnosis of chromophobe RCC. The expression profile of renal cell tumours was established using the Affymetrix HG U133 Plus 2.0 microarray. After performing hierarchical clustering we selected the best 50 genes and analysed 24 of them by reverse transcriptase-polymerase chain reaction. TMC5, RBM35, SPINK7, CD82/KAI1 and GLIS3 were expressed specifically in chromophobe RCCs. Immunohistochemical studies confirmed the specificity of CD82/KAI1. Analysis of tissue microarrays containing all major types of renal neoplasm revealed immunopositivity for CD82/KAI1 in 78% (69/88) of chromophobe RCCs but in only 3% (6/220) of conventional or clear cell RCCs. All 90 ROs and 171 papillary RCCs were immunonegative for CD82/KAI1. To confirm the specificity of antibody by immunoblotting, we transfected HEK293 cells with an expression vector containing the full-length CD82/KAI1. CD82/KAI1 is an excellent marker for distinguishing chromophobe RCCs from other types of renal cell tumours, especially from ROs with overlapping phenotype.