We have found that distamycin A can bind to DNA duplexes containing the (6-4) photoproduct, one of the major UV lesions in DNA, in spite of the changes caused by photoproduct formation in the chemical structure of the base moiety and the local tertiary structure of the duplex. Distamycin binding was analyzed in detail using 14-mer duplexes. Curve fitting of the CD titration data and induced CD difference Spectra revealed that the binding stoichiometry changed from 1:1 to 2:1 with the photoproduct formation. Melting curves of the drug-DNA complexes also supported this stoichiometry.