Thin films of the conducting polymer poly(3,4-(1-azidomethylethylene)dioxythiophene) tosylate (PEDOT−N3) can be functionalized by reaction with alkynated reagents in aqueous solutions. Reaction in pure water resulted in surface specific modification of PEDOT−N3 films, whereas both surface and bulk reaction was achieved in solvent mixtures of water and DMSO. These reaction patterns were confirmed by a combination of AFM and XPS measurements on the front- and back-side of the film. The phenomenon is attributed to a strong dependence of the swelling of PEDOT−N3 on the solvent mixture used. Liquid AFM studies showed increasing film thickness with increasing DMSO content, with the measured thickness in pure DMSO being >250% of the thickness in pure water. A similar, but less pronounced, behavior was observed for unmodified poly(3,4-ethylenedioxythiophene) tosylate (PEDOT). High-density grafting of a number of alkynated compounds onto PEDOT−N3 was achieved via controlled swelling of the polymer. In particular, grafting of alkynated poly(ethylene glycol) (PEG) was optimized to minimize protein adsorption to the conductive polymer surface. Intermediate swelling of PEDOT−N3 during the reaction, using ∼50% DMSO, resulted in the formation of a dense PEG surface layer with low protein adhesiveness without adversely affecting the conductive properties of the film.