A detailed analysis of loss of heterozygosity in 40 sporadic renal cell carcinomas was performed by using 30 restriction fragment length polymorphism markers which were mapped on the short arm of chromosome 3. A total of 30 of 38 informative cases (79%) showed loss of heterozygosity at one or more loci. Two commonly deleted regions have been identified at 3p13-14.3 and 3p21.3. One of them (at 3p13-14.3) spans the breakpoint of the (3;8) translocation in hereditary renal cell carcinoma previously reported (A. J. Cohen et al., N. Engl. J. Med., 301:592-595, 1979). The second common region of deletion at chromosome 3p21.3 encompasses D3F15S2, at which a high incidence of loss of heterzygosity in renal cell carcinoma has been reported. In addition to the gene at 3p25 being responsible for the hereditary type of renal cell carcinoma in patients with von Hippel-Lindau disease, our results suggest that at least two tumor suppressor genes for sporadic renal cell carcinoma exist on the short arm of chromosome 3.