A degradable poly(ethylene glycol)-diacrylate (PEGDA) hydrogel system was developed using simple macromer formulations and visible light initiated thiol-acrylate photopolymerization. In addition to PEGDA, other components in this gelation system include eosin-Y as a photo-sensitizer, bi-functional thiol (dithiothreitol, DTT) as a dual-purpose co-initiator and cross-linker, and N-vinylpyrrolidone (NVP) as a co-monomer. Gelation was achieved through a mixed-mode step-chain growth polymerization mechanism under bright visible light exposure. Increasing photo-sensitizer or NVP concentrations accelerated photo-crosslinking and increased final gel stiffness. Increasing bi-functional thiol content in the prepolymer solution only increased gel stiffness to some degree. As the concentration of thiol surpassed certain range, thiol-mediated chain-transfer events caused thiol-acrylate gels to form with lower degree of cross-linking. Pendant peptide, such as integrin ligand RGDS, was more effectively immobilized in the network via a thiol-acrylate reaction (using thiol-bearing peptide Ac-CRGDS. Underline indicates cross-linkable motif) than through homo-polymerization of acrylated peptide (e.g., acryl-RGDS). The incorporation of pendant peptide comes with the expense of a lower degree of gel cross-linking, which was rectified by increasing co-monomer NVP content. Without the use of any readily degradable macromer, these visible light initiated mixed-mode cross-linked hydrogels degraded hydrolytically due to the formation of thiol-ether-ester bonds following thiol-acrylate reactions. An exponential growth relationship was identified between the hydrolytic degradation rate and bifunctional thiol content in the prepolymer solution. Finally, we evaluated the cytocompatibility of these mixed-mode cross-linked degradable hydrogels using in situ encapsulation of hepatocellular carcinoma Huh7 cells. Encapsulated Huh7 cells remained alive and proliferated as time to form cell clusters. The addition of NVP at a higher concentration (0.3%) did not affect Huh7 cell viability but resulted in reduction of cell metabolic activity, which was accompanied by an elevated urea secretion from the encapsulated cells. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3813–3827, 2014.