The interaction between poly(3,4-ethylenedioxythiophene), a conducting polymer with excellent electrical and electrochemical properties, and plasmid DNA has been investigated using electrophoresis, UV-visible and CD spectroscopy, and quantum mechanical calculations. Analyses of mixtures with different DNA:polymer mass ratios indicate that, in all cases, interactions form immediately and induce structural alterations in DNA. Furthermore, the existence of interactions between poly(3,4-ethylenedioxythiophene) and specific nucleotides sequences has been evidenced by adding restriction enzymes to the mixtures. In contrast, interactions between DNA and poly(3-methylthiophene), a similar polyheterocyclic conducting polymer but without hydrogen bonding acceptors, are weak or do not exist. These results suggest that, in addition to non-specific electrostatic interactions between the charged phosphate groups of DNA and the positively charged fragments of the conducing polymers, specific hydrogen bonding interactions play a crucial role. The ability of 3,4-ethylenedioxythiophene units to form hydrogen bonds with the methylated analogues of DNA bases has been examined in different environments using MP2/6-31G(d) and MP2/6-311++G(d,p) calculations. Results indicate that, in environments with low polarity, the formed interactions are significantly stronger than those reached by unsubstituted thiophene and similar to those established by pyrrole. However, in polar environments (aqueous solution) 3,4-ethylenedioxythiophene provides stronger interactions with nucleic acids than both thiophene and pyrrole. These theoretical results are fully consistent with experimental observations. © 2009 Elsevier Ltd. All rights reserved.