Protein binding in hydrogels adversely affects their performance and can interfere with their usage in several biomedical applications including contact lenses. In this study we focus on understanding and modeling the mechanisms of protein transport in hydrogels, specifically focusing on the effect of protein concentration and gel crosslinking on transport. Specifically, we focus on lysozyme, the most abundant protein in tear fluid, and hydrogels of poly-hydroxyethyl methacrylate (p-HEMA), a common contact lens material. Protein uptake experiments with gels of different thicknesses showed a time scale increase as the square of the thickness suggesting diffusion controlled transport. Partition coefficient was found to be dependent on the equilibrium concentration of lysozyme, and also on the degree of crosslinking. Since transport is related to mesh size, gel modulus was obtained for various crosslinkings and utilized to estimate the mesh size. The transport data were fitted to a diffusion model and the fitted diffusivity was compared to diffusivity predicted from a model based on hydrogel mesh size. Both protein absorption and desorption data fitted the diffusion model with the same value of diffusivity, but the experimentally measured diffusivities were significantly smaller than those estimated on the basis of the gel mesh size. Models were modified to take into account protein binding to the polymer but the modified predictions were still larger than the measured values. The results of this study could assist in the development of contact lens materials that exhibit minimal protein binding, in designing cleaning regimens for protein removal from contact lenses, and in applications related to protein binding in several other biomaterials. (C) 2012 Elsevier Inc. All rights reserved.