We have used differential‐display PCR (DD‐PCR) to compare renal‐cell carcinoma (RCC) and normal kidney gene expression with the aim of identifying genes specifically associated with RCC. Using a modified DD‐PCR approach, which was non‐radioactive, quicker and simpler than the conventional method, 24 cDNA samples were clearly up‐ or down‐regulated in RCC tissue from 4 patients. Fourteen of these showed high similarity to a number of known genes. Eight of these cDNA clones were chosen for further analysis. These were a regulator of G‐protein signalling (RGS‐5), Notch‐3, Na,K‐ATPase α subunit, HLA class II antigen, ETS‐like protein, transforming growth factor β–stimulated clone (TSC‐22), bladder cancer–related protein (BC10) and adipophilin. Semi‐quantitative RT‐PCR using specific primers to each of these genes confirmed differential expression in 67% to 83% of a further 12 RCC and normal kidney paired samples from 7 of the 8 cDNA clones. Northern analysis further confirmed the up‐regulation in expression of RGS‐5 and Notch‐3 in RCC. Further characterisation of these differentially expressed genes should lead to a better understanding of the changes that occur at the molecular level during RCC development and progression. Int. J. Cancer 88:726–732, 2000. © 2000 Wiley‐Liss, Inc.