In light of cell sourcing issues and the lack of a bioreactor comparable to the body, many in the field of tissue engineering have focused their efforts on designing biomaterials capable of in situ regeneration. The theory is that, by using the body as both the bioreactor and the source for cell infiltration, scaffolds composed of bioresorbable materials can be remodeled into native tissue. Thus, research into the effects of such materials on the host immune response is increasingly important. This study applies an immunotoxicological approach to evaluate the effects of electrospun blends of polydioxanone (PDO) and collagen type I on murine innate and acquired immune responses. Results indicated that these materials had few effects on innate immune responses, yet they produced significant immunomodulatory effects in multiple end-points evaluating both branches of acquired immunity (i.e., cell-mediated and Immoral immunity). Specifically, collagen content appeared to be responsible for suppression of cell-mediated immunity, while blends of PDO and collagen appeared to be more suppressive of antibody-forming cell responses than either PDO or collagen alone. These results demonstrate the importance of completing evaluations into the immunotoxicological effects of biomaterials, and they suggest that such testing should become a primary focus when evaluating a material's potential for use in tissue engineering applications. (C) 2009 Wiley Periodicals, Inc. J Biomed Mater Res 93A: 793-806, 2010