Mussel adhesive moiety, catechol, has been utilized to design a wide variety of biomaterials. However, the biocompatibility and biological responses associated with the byproducts generated during the curing process of catechol has never been characterized. An in situ curable polymer model system, 4-armed polyethylene glycol polymer end-capped with dopamine (PEG-D4), was used to characterize the production of hydrogen peroxide (H₂O₂) during the oxidative crosslinking of catechol. Although PEG-D4 cured rapidly (under 30 seconds), catechol continues to polymerize over several hours to form a more densely crosslinked network over time. PEG-D4 hydrogels were examined at two different time points; 5 min and 16 hrs after initiation of crosslinking. Catechol in the 5 min-cured PEG-D4 retained the ability to continue to crosslink and generated an order of magnitude higher H₂O₂ (40 µM) over 6 hrs when compared to 16 hrs-cured samples that ceased to crosslink. H₂O₂ generated during catechol crosslinking exhibited localized cytotoxicity in culture and upregulated the expression of an antioxidant enzyme, peroxiredoxin 2, in primary dermal and tendon fibroblasts. Subcutaneous implantation study indicated that H₂O₂ released during oxidative crosslinking of PEG-D4 hydrogel promoted superoxide generation, macrophage recruitment, and M2 macrophage polarization in tissues surrounding the implant. Given the multitude of biological responses associated with H₂O₂, it is important to monitor and tailor the production of H₂O₂ generated from catechol-containing biomaterials for a given application.