The objective of this work was to create 3D hydrogel matrices with defined mechanical properties as well as tunable degradability for use in applications involving protein delivery and cell encapsulation. Therefore, we report the synthesis and characterization of a novel hydrolytically degradable poly(ethylene glycol) (PEG) hydrogel composed of PEG vinyl sulfone (PEG-VS) cross-linked with PEG-diester-dithiol. Unlike previously reported degradable PEG-based hydrogels, these materials are homogeneous in structure, fully hydrophilic, and have highly specific cross-linking chemistry. We characterized hydrogel degradation and associated trends in mechanical properties, that is, storage modulus (G'), swelling ratio (Q(M)), and mesh size (xi). Degradation time and the monitored mechanical properties of the hydrogel correlated with cross-linker molecular weight, cross-linker functionality, and total polymer density; these properties changed predictably as degradation proceeded (G' decreased, whereas Q(M) and xi increased) until the gels reached complete degradation. Balb/3T3 fibroblast adhesion and proliferation within the 3D hydrogel matrices were also verified. In sum, these unique properties indicate that the reported degradable PEG hydrogels are well poised for specific applications in protein and cell delivery to repair soft tissue.