Peripheral blood lymphocytes of patients with Fanconi's anemia (FA) were tested for their susceptibility to chromosome breakage by cis-platinum(II)-diamminedichloride [cis-Pt(II)], cis-platinum(IV)diamminetetrachloride [cis-Pt(IV)], and trans-platinum(IV)diamminetetrachloride [trans-Pt(IV)]. Low doses (0.1 microgram/ml) of the DNA-DNA cross-linking agents cis-Pt(II) and cis-Pt(IV) dramatically increased the chromosome breakage level in FA cultures without affecting the controls. The predominantly DNA-protein cross-linking compound trans-Pt(IV), however, was much less effective in producing chromosomal damage in FA. The differential response of FA cells to cis-Pt(IV) and trans-Pt(IV) suggests that the high susceptibility of FA to bifunctional cross-linking agents is due to an impairment of the cells to tolerate DNA-DNA cross-links, rather than DNA-protein cross-links.