Most renal cell carcinomas (RCC) show only simple chromosomal changes. However, a more complex cytogenetic pattern has been found in a subgroup of aggressive RCC, indicating that further accumulation of chromosome changes could play a role in tumour progression. To explore the possible mechanisms behind cytogenetic evolution in RCC, a parallel assessment of chromosome mutations and mitotic segregation pattern in eight tumours was performed. In the majority of cases, no abnormalities in the cell division machinery were found and the rate of alterations in chromosome copy number, as measured by interphase FISH, was similar to that in non-neoplastic cells. This was reflected by relatively simple karyotypes, with little cytogenetic intratumour heterogeneity. In contrast, another group of tumours exhibited several cytogenetically related clones with additional structural chromosomal changes at two or more ploidy levels and a frequency of copy number alterations that was higher than in normal cells. In these cases, the telomere repeat sequences were abnormally short and chromosomal breakage-fusion-bridge events were observed at cell division, as well as multipolar configurations and supernumerary centrosomes. Abnormalities of the cell division machinery may thus contribute to the evolution of complex karyotypes and genetic intratumour heterogeneity in a subgroup of RCC.