Recent studies have shown that the deletion of chromosome 3p or the loss of DNA sequences at 3p is generally associated with the development of renal cell carcinoma (RCC). However, chromosome analysis of some papillary RCCs suggested that this type of tumor differs genotypically from the most common nonpapillary RCCs. Therefore, by using cytogenetic and molecular genetic approaches, we examined human papillary and nonpapillary RCCs for the loss of heterozygosity or homozygosity at the short arm of chromosome 3. The constitutional heterozygosity for the DNF15S2 locus and for one allele of the c-erbA beta and the c-raf-1 proto-oncogenes was lost in nonpapillary RCCs, whereas both alleles were retained in each papillary RCC analyzed. We conclude that the loss of DNA sequences at the chromosome 3p region is a genomic change occurring consistently in nonpapillary RCCs, but never occurring in papillary RCCs.