The binding of the antitumoral drug actinomycin D to single- and double-stranded DNA was investigated using molecular modeling in the frame of MM + molecular mechanics and AM1 semi-empirical method. Two other programs, especially conceived to analyze hydrogen-bonding patterns in biological macromolecules, HBexplore, based on geometrical criteria and SHB_interactions, based on quantum-chemical criteria (Mulliken overlap populations), were also used. The results account for the non-cooperative intercalative binding process previously investigated, and outline the contribution of specific hydrogen bonding as well as C H···O(N) and other atom–atom intermolecular interactions to the stabilization of the actinomycin D–DNA complexes. They also support the hemi-intercalation model proposed in literature for the actinomycin D–ssDNA complex.