The effect of two simulated biological environments (protein-free and protein-containing) on ion uptake and physical properties of PVA/PVP hydrogels were explored in this work. It was found that over the immersion period in both media, wet mass of the hydrogels decreased and compressive moduli increased, likely due to increased polymer content with water loss as the hydrogels equilibrated with water. These changes were independent of polymer content and immersion medium. However, dry mass of the hydrogels increased dramatically when immersed in protein-free medium, changing only moderately in protein-containing medium. The increase in dry mass was attributed to ion uptake from immersion medium, as confirmed by EDXA. We postulate that differences between ion uptake in protein-free versus protein-containing medium is likely the result of serum proteins in the protein-containing medium adsorbing to the surface, inhibiting transport of ions into the hydrogel.