Although many biodegradable polymers, such as poly-L-lactic acid and poly-L-glycolic acid, are preferentially composed of biological residues normally present in the human body, implants made of these materials often trigger inflammatory and fibrotic responses. Unfortunately, the mechanisms involved in degradable material-mediated tissue responses remain largely unknown. Using animal implantation and cell culture system models, we found a strong correlation between the rate of material degradation and the degree of inflammatory response to material implants. Furthermore, we have identified that both water-soluble and water-insoluble degradation products are potent triggers of phagocyte activation, including at the least, superoxide production. These results support a new concept that slow degradation may improve the biocompatibility of degradable drug-releasing particles and tissue engineering scaffolds.