Background: This study directly compared optical coherence tomography (OCT) and histopathology for the assessment of vascular response to first-and second-generation drug-eluting stents. Methods and Results: Sirolimus-, everolimus-, and biolimus-eluting stents (SES, EES, and BES, respectively) were randomly implanted into the coronary arteries of 12 porcine. OCT was conducted after implantation: at 1, 3, and 6 months; histopathology was assessed at 3 and 6 months. At 1-month OCT, EES had the highest neointimal area (NA) and lowest neointimal unevenness score (NUS). At 6 months, NA and NUS were equivalent among the stent types. Delta NA from 1 to 6 months was lowest for EES, and Delta NA correlated with the histopathological inflammation score at 6 months, which was highest for SES (P<0.001). The mean signal intensity (MSI) and the attenuation were different for the stent types at 3 months, and were associated with inflammation score. Moderate diagnostic efficiency for measuring MSI was found, with an optimal cut-off of 6.88 predicting a high (>= grade 3) inflammation score. Conclusions: EES had the greatest uniformity and the least neointimal proliferation and were associated with less persistent inflammation. OCT provides accurate morphometric data; furthermore, quantitative measurement of the optical properties may help assess histological inflammation, which was more predominantly associated with SES than with EES and BES.