Bladder carcinogenesis remains unclear despite the identification of chemical, environmental and genetic factors. It has recently been reported that the chromosomal region 12q13-q15, containing crucial cancer genes such as MDM2, CDK4 and GLI, is amplified in bladder cancer. In the same region are also located the genes of the locus HOX C, flanked by keratin genes whose protein product may be a prognostic marker of bladder cancer. The HOX genes constitute a network of transcription factors controlling embryonal development and play an important role in crucial adult eukaryotic cell functions. The molecular organization of this 39-gene network is unique in the genome and probably acts by regulating phenotypical cell identity. We have analysed the expression of the whole HOX gene network in pairs of normal-tumour bladder and in tumoral biopsies. Comparison between normal urothelium and bladder tumour has identified dramatic variations of expression in a block of three genes (HOX C4, HOX C5 and HOX C6) localized in the HOX C locus on the chromosome 12q13 and in the paralogous group 11 HOX genes, involved during normal development in the formation of the urogenital system. These data suggest a key involvement of the HOX gene network, and especially the locus C, in bladder cancer.