The foreign body reaction (FBR) is of great importance for the function and turnover of biomaterial scaffolds. The development of biological tools that modulate the FBR will augment scaffold functionality and benefit regenerative medicine. The human cytomegalovirus encodes a functional homolog of the potent anti-inflammatory human cytokine interleukin-10 (cmvIL-10). We hypothesized that cmvIL-10 downmodulates the FBR, impairing degradation of biomaterial. We studied the effect of cmvIL-10 on the FBR to subcutaneously implanted hexamethylenediisocyanate-crosslinked dermal sheep collagen (HDSC) discs in rats. CmvIL-10 impaired macrophage influx, vascularization and ingrowth into the discs up to 21 days. It also impaired the formation of giant cells and the degradation of HDSC. At day 10, deposited fibrin fibers were still present in cmvIL-10 discs. Impaired collagenase activity coincided with the impaired HDSC degradation. These results indicate that cmvIL-10 downmodulates the FBR, impairing the progression of the FBR. This study demonstrates the feasibility of interleukin-10 as a biomolecular tool in biomaterials for regenerative medicine.