Genomic DNA from 53 primary human renal cell tumors was screened for the presence of mutations in the tumor suppressor gene p53, using the polymerase chain reaction and single-strand conformation polymorphism analysis, followed by direct sequencing of DNA. Five cases showed mobility shifts. Sequencing of these samples revealed two cases of nonsense mutations (codons 182, 192), one case of a missense mutation (codon 285), and two cases of silent mutations at codon 213. The frequency of mutations altering the p53 (3/53 = 6%) was low when compared with the reported frequencies (15% to 65%) of allelic loss of 17p (location of p53) in renal cell cancers, suggesting the possible existence of another tumor suppressor gene in the region of the p53 gene, which when mutated is associated with these cancers. All three tumors with p53 mutations were cases with poor prognosis, i.e., highest pathological grade and/or advanced Robson stage. The human equivalent of the murine double-minute-2 was not amplified in the renal cell tumors. In summary, alterations of p53 may be associated with the development of renal cell carcinoma of higher grade and/or stage.