A very peculiar case of differential cell response towards polysiloxane surfaces of very similar composition is investigated. Poly(hydroxymethylsiloxane) (PHMS) surfaces treated either by O(2)-plasma or 6 keV Ar(+)-beams have been used to test the adhesion, proliferation and spreading of human fibroblasts. The surface chemical structure and nanomorphology were investigated by means of X-ray photoelectron spectroscopy (XPS), surface free energy measurements and atomic force microscopy (AFM). In spite of the close compositional and morphological similarity of the modified surfaces, the viability of the adhered cells, evaluated by means of optical microscopy and epifluorescence microscopy, was found to be very different in the two cases. The study of the features of the adsorbed protein adlayer on the two types of surfaces was performed by XPS and AFM and indicated that the overall cell behavior is connected to a quite different protein aggregation process, occurring respectively on the plasma- and Ar(+)-modified polysiloxane surfaces. It is suggested that the specific biological response of the modified surfaces is determined by the chemical structure at the nanometric level.