Animal and clinical studies have demonstrated late regression of in-stent neointima. This study was performed to identify the temporal changes in the in-stent neointimal constituents responsible for late regression. NIR stents were implanted in porcine coronary arteries (size of stent (in mm) to size of artery (in mm) approximately equal to 1.1) and harvested at 2 months and 6 months (n = 6 stents/group). Histopathologic analyses included morphometric analysis, smooth muscle cell density, and extracellular matrix contents. Compared with the findings at 2 months, at 6 months there was a significant reduction in area stenosed (from 21 +/- 3% to 14 +/- 1%, P < 0.05) and neointimal thickness (from 0.2 +/- 0.03 mm to 0.03 +/- 0.02 mm, P < 0.05), despite similar injury scores (0.05 +/- 0.06 at 2 months and 0.36 +/- 0.29 at 6 months). This regression was accompanied mainly by a reduction in proteoglycan (from 24 +/- 19% to 5 +/- 8%, P = 0.05), with no change in smooth muscle cell density (71 +/- 7 compared with 76 +/- 23/high power field) or collagen content (25 +/- 19% compared with 25 +/- 19%). The study confirmed the regression of in-stent neointima, which was mainly attributable to a reduction in proteoglycan content, resembling the natural healing response.