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The lifetime and efficacy of tissue engineering scaffolds are determined by the foreign body response. In this study, we investigated the <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> effects of capsaicin to reduce biomaterial\u2010induced fibrosis. RAW 264.7 cells cultured on PLGA films with capsaicin responded with significant (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) upregulation in M2 markers arginase\u20101 and IL\u201010 and downregulation of M1 markers iNOS and IL\u201012, demonstrating the potential of capsaicin to reduce PLGA\u2010induced inflammation. Subsequent animal studies were conducted where PLGA and capsaicin\u2010embedded PLGA discs were implanted in C57BL\/6 mice for 2 and 14 days. Explanted capsaicin\u2010embedded PLGA implants had 40% less collagen than PLGA\u2010only implants. Capsaicin caused a 35% increase in IL\u201010 which played a key role in suppressing fibrosis. Macrophage phenotype markers in peritoneal cells and adherent cells were unaffected by capsaicin; however, capsaicin suppressed the myofibroblast marker \u03b1\u2010SMA in adherent cells by day 14. Overall, our results revealed that capsaicin reduced biomaterial\u2010induced fibrosis and demonstrates that capsaicin has the potential to extend the lifetime of a tissue engineering scaffold when used in long\u2010term drug release applications from hydrophobic biomaterials. \u00a9 2018 Wiley Periodicals, Inc. 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