Previous studies have suggested that increased malignant potential might be related to increased genomic instability, but this issue still remains controversial. We tested this hypothesis in a human tumour spontaneous metastasis model, using six clones and variants isolated from the parental poorly metastatic M4Be melanoma cell line, and expressing various metastatic abilities. The spontaneous rates of mutation to ouabain resistance measured in these cells by Luria and Delbrück fluctuation analysis correlated with the metastatic ability of the cells: moderately and highly metastatic cells showed spontaneous mutation rates 10 to 50 times higher than those of poorly metastatic cells. Genomic instability at the chromosome level was assessed by searching for accumulated structural abnormalities in the moderately and highly metastatic cell lines. All the cell lines appeared hypertriploid, and showed comparable modal numbers and great chromosome dispersion. Unstable DNA amplification in the form of double minute chromosomes was shown in one of the four poorly metastatic cell lines, and in a significantly higher proportion of the cells of two of the three metastatic cell lines. Abnormal chromosomes were demonstrated in all cell lines, with markers involving specific rearrangements of chromosomes 1, 6, 7, 8, 9, 11, 14 and 15, as frequently observed in human melanoma cells. Clonal markers were present in all cell lines, documenting the common origin of all variants and clones, and specific marker amplification was noticed in highly metastatic cells compared to poorly metastatic lines. These results suggest that human tumour progression might be accompanied both by an increase in genomic instability and by accumulation of karyotypic abnormalities.