We have studied the cytotoxicity and DNA cross-linking induced by cis-diamminedichloroplatinum(II) (cis-Pt) in a normal, a simian virus 40-transformed, and eight tumor cell lines of human origin. These cell strains were chosen on the basis of their Mer phenotype, i.e., their ability to repair DNA containing 6O-alkylated guanine. The cytotoxicity was assayed by measuring the inhibition of cell proliferation after a two-hr treatment of the cell cultures with cis-Pt concentrations ranging from 1 to 50 microM. DNA-protein cross-links and DNA interstrand cross-links were measured by DNA alkaline elution after a two-hr treatment with 10 or 20 microM cis-Pt. The different cell lines differed in sensitivity to cis-Pt. The drug concentration required to produce the same inhibition of growth varied over a 10-fold range. Cell sensitivity correlated with DNA interstrand cross-linking (r = 0.83; p less than 0.01) better than with DNA-protein cross-linking (r = 0.75; p less than 0.05). There was no correlation between cell sensitivity or DNA interstrand cross-linking and the Mer phenotype. The lack of relationship between the extent of DNA interstrand cross-linking by cis-Pt and the Mer phenotype suggests that this repair mechanism does not remove from DNA cis-Pt monoadducts that have the potential to form interstrand cross-links.