Background:We aimed to describe the frequency of vascular inflammatory reactions with second generation drug eluting stents (DES) compared to first generation DES, and analyze the impact on inflammation and neointimal proliferation in a porcine coronary model. Methods: A total of 26 stents (7 multi-link VISION, 6 CYPHER, 6 TAXUS and 7 XIENCE V) were deployed in the coronary arteries of 10 domestic swine for 28 days, after which each stent was harvested and processed (divided into 8 or 9 segments) for histomorphometric analysis. Results: A total of 202 histological segments [146 DES and 56 bare metal stents (BMS)] were included in this study. The mean neointimal thickness was significantly reduced in the DES group compared to the BMS group. The DES group had higher injury scores (DES = 0.99  0.79 versus BMS = 0.67  0.44, p < 0.004), inflammatory scores (DES = 2.09  1.54 versus BMS = 0.64  0.98, p < 0.001) and presence of para-strut granulomas (DES = 35% versus BMS = 2%, p < 0.001). In logistic regression analysis, the presence of para-strut granulomas correlated with an area of stenosis > 50% (RR: 6.11, 95% CI: 2.97 to 12.59, p = 0.001). In the DES group, the second generation stents had a lower neointimal area (XIENCE V: 1.64  0.90 mm2) compared to the first generation stents (TAXUS: 2.36  1.56 mm2, p = 0.005; CYPHER 2.78  1.82mm2, p = 0.001). The XIENCE V stents had lower inflammatory scores and lower frequency of para-strut granulomas compared to the first generation stents. Conclusions: Second generation DES had a lower incidence of vascular inflammatory reactions compared to first generation DES. This biological phenomenon appears to influence the patterns of neointimal formation.