The aim of this study was to compare dextran and Poly(l-lactide) (PLLA) polymer stent coatings as mediators for sirolimus (SRL) drug elution in a porcine coronary model. The bare metal stent (BMS) surface was first coated with a layer of SRL and then either dextran (DSS, a natural polymer) or PLA (PSS, a synthetic polymer). The release velocity of SRL was slightly faster in DSS than PSS over the first 7 days (78.5% and 62.3%, respectively, n = 10, p < 0.05) and continued to 28 days in both groups. The contact angle was dramatically decreased in DSS (38.7° ± 1.24) compared to BMS and PSS groups (72.7° ± 5.32 and 81.1º ± 1.70, respectively, n = 10, p < 0.05). Smooth muscle cell migration was arrested in both the DSS and PSS-treated groups compared to that in the nontreated group (4.2% ± 0.31, 5.8% ± 0.60, 80.0% ± 4.4, respectively, n = 10, p < 0.05). In the animal study, there were no significant differences in the injury score, the internal elastic lamina, and the lumen area among the groups. However, percent area stenosis was significantly decreased in the SRL-containing group (27.5% ± 2.52 in DSS and 27.9% ± 3.30 in PSS) compared to BMS (35.9% ± 3.51, p < 0.05). The fibrin score was higher in the PSS (2.9 ± 0.31) than BMS (2.1 ± 0.12) and DSS (2.5 ± 0.66). The inflammation score in the DSS (0.7 ± 0.21) was similar to that in the BMS (0.7 ± 0.12), which was dramatically lower than that PSS (1.5 ± 0.18, p < 0.005). Immunofluorescence analysis revealed that endothelialization was increased and inflammation prevented in the DSS. These results suggest that dextran may be useful for the fabrication of drug eluting stent as an alternative existing synthetic polymer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 301-310, 2017.