Human renal cell carcinogenesis is usually accompanied by dedifferentiation processes including the loss of expression of tissue specifically expressed genes. Based on the hypothesis that these dedifferentiation processes might be attributed to a functional change in tissue specific transcription factors, we have analyzed the expression and function of the tissue specific transcription factor HNF4 alpha in human renal cell carcinomas. By Western blot analysis and gel retardation assay using HNF4 alpha specific antibodies, we observed that in most cases the amount as well as the binding activity of HNF4 is reduced in the tumor samples compared to the corresponding normal tissues. Furthermore, we found a clear correlation between the HNF4 alpha binding activity and the amount of another transcription factor (HNF1 alpha), which is thought to be transcriptionally activated by HNF4 alpha. We therefore speculate that disruption of the HNF4 alpha/HNF1 alpha pathway of kidney specific gene expression might be an important molecular mechanism in renal cell carcinogenesis.