The outcome of patients with renal cell carcinoma is limited by the development of metastasis after nephrectomy. To evaluate the genetic basis underlying metastatic progression of human renal cell carcinoma in vivo, we performed a comparative genomic hybridization analysis in 32 clear-cell renal-cell carcinoma metastases. The most common losses involved chromosomes 3p (25%), 4q (28%), 6q (28%), 8p (31%), and 9p (47%). The most common gains were detected at 17q (31%) and Xq (28%). There was one high-level gene amplification at chromosome 11q22-23. The mean number of aberrations in lymph node (4.8 +/- 2.8) and lung metastases (6.2 +/- 4.0) was lower than in other hematogenous metastases (11.5 +/- 8.7, P < 0.05), suggesting that hematogenous dissemination is linked to an acquisition of complex genomic alterations. As genetic differences between primary tumors and metastases give information on genetic changes that have contributed to the metastatic process, relative DNA sequence copy number changes in 19 matched tumor pairs were compared. Genomic changes, which frequently occurred in metastases but not in the corresponding primary tumor were losses of 8p and 9p and gains of 17q and Xq. An abnormal function of genes in these regions may contribute to the metastatic process. According to a statistical analysis of shared genetic changes in matched tumor pairs, a high probability of a common clonal progenitor was found in 11 of 19 patients (58%). Six metastases (32%) were genetically almost completely different from the primary, suggesting that detection of genomic alterations in primary tumors gives only a restricted view of the biological properties of metastatic renal cell carcinoma.