To investigate the possible role of genomic aberrations of chromosome 9p21-22 in the tumorigenesis of human renal cell carcinoma (RCC), 10 RCC cell lines, 55 primary RCCs and 5 metastatic lesions were studied by Southern blotting and polymerase chain reaction-based analysis. Nine of 10 RCC cell lines showed a homozygous deletion of MTSI/CDKN2/(p16), while only 1 in 55 primary tumors had this deletion. Loss of heterozygosity on 9p21-22 was observed in 5 of 10 informative primary RCCs from patients with metastasis, but in only 4 of 31 informative tumors (13%) without metastasis (P = 0.025). Futhermore, 3 of 5 metastatic tumors (60%) showed hemi- or homozygous deletion of MTSI/CDKN2. These results indicate that the 9p21-22 deletion may be a relatively late event in RCC tumorigenesis and could be associated with RCC metastasis.