In this study, we provide a new pharmacological treatment, which may prevent scar formation on wound healing and/or plastic surgery wounds. We used prednisolone to reduce scar formation in wound excision. To prolong the drug effect, prednisolone of different amounts were encapsulated in biodegradable poly(D,L-lactide) (PDLL) microspheres. In the in vitro cell healing study, prednisolone was markedly effective in reducing the growth rate of fibroblast cells according to electric cell-substrate impedance sensing results. At a higher density of prednisolone, a slower growth rate was observed (ANOVA, p < 0.05). In rat models of skin wound healing studies, results show that in postsurgery days 7 and 14, all of the wound fibrosis areas administered with 0.5 and 5 mM of prednisolone-loaded PDLL microspheres (PPM) were decreased by 6–116% compared with those of the control groups (ANOVA, p < 0.05). Adding the PPM led to reduce IL-1β but increase MMP-9 expression levels as compared with the control groups (ANOVA, p < 0.0001). These results implies that using sustained releasing prednisolone microspheres can regulate ECM generated from fibroblasts, can avoid excess proliferation and reduce the formation of scar tissue during wound regeneration by inhibiting the degree of inflammation. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.