Hydrogels have gained broad acceptance as a class of biocompatible materials. In this paper, we report the topographic patterning and regiospecific functionalization of hydrogel surfaces. Both photolithography and soft lithography are combined in a hybrid process to form these topographic features. By functionalization of a base layer surface followed by lithographic patterning steps, it is possible to introduce chemical functions to specific regions of the patterned surface. The model systems investigated were based on 2-hydroxyethyl methacrylate (HEMA), which is well-known for its low toxicity and widespread use in biomedical applications. Tests of Ni-NTA modified hydrogel surfaces showed successful binding of fluorescently labeled proteins to selected regions of the patterned hydrogel surface. These processes can be expanded to a wide range of monomer systems.