Anthracyclines are widely used in oncology. Both the response and side-effects of anthracyclines are individually variable, but determinants or predictive markers of this variability are not available. We investigated the variability in the expression of the anthracycline targets topoisomerases II (topo II) alpha and beta and its significance for the apoptotic response following exposure to the anthracycline doxorubicin. Only topo II beta protein expression was detected in peripheral blood cells. Usually considered a constitutively expressed protein, topo II beta varied 3-, 18-, and 16-fold on the mRNA, protein and activity levels, respectively, among the volunteers tested. In addition, the expression of topo II beta was modified by several mitogens, suggesting a role in the regulation of cell cycle. Strikingly, topo II beta activity correlated statistically significantly with the apoptotic response in peripheral blood leukocytes exposed to 1 microM doxorubicin. A longitudinal study in a subset of study subjects demonstrated that 30% of the topo II expression variability may be inherited. However, resequencing of the TOP2B gene in 48 unrelated individuals revealed only 8 gene variants, none of them with obvious effects on the expression or protein sequence of topo II beta. Taken together, the apoptotic response to doxorubicin in peripheral blood cells may be mediated by topo II beta. The expression level of topo II beta is intra- and inter-individually variable, and may in part determine the apoptotic response to doxorubicin and other anthracyclines.