Photopolymerizable poly(ethylene glycol) (PEG)- based hydrogels have great potential as in vivo cell delivery vehicles for tissue engineering. However, their success in vivo will be dependent on the host response. The objectives for this study were to explore the in vivo host response and in vitro macrophage response to commonly used PEG-based hydrogels, PEG and PEG containing RGD. Acellular hydrogels were implanted subcutaneously into c57bl/6 mice and the foreign body response (FBR) was compared to medical grade silicone. Our findings demonstrated PEG-RGD hydrogels resulted in a FBR similar to silicone, while PEG-only hydrogels resulted in a robust inflammatory reaction characterized by a thick layer of macrophages at the material surface with evidence of gel degradation. In vitro, bone marrow-derived primary macrophages adhered well and similarly to PEG-based hydrogels, silicone, and tissue culture polystyrene when cultured for 4 days. Significantly higher gene expressions of the proinflammatory cytokines, TNF-alpha and Il-1beta, were found in macrophages seeded onto PEG compared to PEG-RGD and silicone at 1 and 2 days. PEG hydrogels were also shown to be susceptible to oxidative biodegradation. Our findings indicate that PEG-only hydrogels are proinflammatory while RGD attenuates this negative reaction leading to a moderate FBR.