Overexpression of endothelin-1, endothelin-A- and endothelin-B-receptors has been shown in various human tumors. To assess the role of the ET-axis in bladder cancer, we analyzed its expression in tumor specimens and bladder cancer cell lines. Samples were obtained by radical cystectomy at two urologic institutions. ET-axis expression was investigated by reverse-transcription polymerase chain reaction (RT-PCR) (n=22) and immunohistochemistry (n=42). Additionally, four bladder cancer cell lines were analyzed. RT-PCR analysis for the ET-axis showed positive signals in the majority of cDNA probes. Signals for endothelin-1 (ET-1), endothelin-A-receptor (ET(A)R) and endothelin-B-receptor (ET(B)R), as identified semiquantitatively and by densitometry, were found in 22, 22 and 15 of 22 cases, respectively. Immunohistochemistry revealed expression of ET-1, ET(A)- and ET(B)-receptor in 18, 29 and 37 of the 42 cases, respectively, whereas normal urothelium was negative. All cell lines expressed ET-1, and all but the RT-112 cell line produced ETAR, whereas no cell line expressed ET(B)R. The identification of the ET-axis at the mRNA and protein level in the majority of bladder tumor samples suggests a role in the carcinogenesis of bladder cancer. Further studies on regulation of the ET-axis and the future use of selective ET(A)-receptor inhibitors for targeted molecular therapy in bladder cancer are in progress.