p73, a protein that has substantial structural and functional similarity to p53, has recently been identified. It was found to be monoallelically expressed in all cell lines and normal individuals tested. To elucidate its role in cancer development and as a potential imprinted tumor suppressor, we investigated the allele-specific expression of the human p73 gene in 28 cases of renal cell carcinoma and its imprinting status in fetal pancreatic and thymic tissues. Of 12 informative pairs of renal cell carcinoma and matched normal tissues identified by StyI restriction fragment length polymorphism (RFLP) in exon 2, p73 showed monoallelic expression in 11 out of 12 normal tissues but biallelic expression in 8/12 and switched allele expression in 2/12 of the matched corresponding cancers. An imprinting study of the p73 gene in two families using a newly identified exonic BanI RFLP indicated that expression of p73 was limited to the maternal allele in RNA from fetal pancreas and thymus, demonstrating that p73 is imprinted in at least these two tissues. These findings strongly suggest that loss of imprinting or switching of allelic expression of the p73 gene is associated with the development of renal cell carcinoma.