Raman scattering was shown to be an efficient tool for analyzing the interactions of natural (phosphate) and chemically modified phosphorothioate oligodeoxynucleotides with an amphipathic cationic peptide adopting an α-helix structure in aqueous environment. Examination of the Raman spectra recorded from different partners and their complexes, leads us to conclude that these interactions cannot be interpreted within a restricted electrostatic framework. The cationic peptide can undergo an order-to-disorder transition upon interaction with oligodeoxynucleotides. Furthermore, it can interact with different structural fragments of their partners (nucleoside, backbone). However, these interactions appear to be sequence-dependent and stronger with natural oligodeoxynucleotides compared to their chemically modified analogues.