OBJECTIVES This study sought to evaluate the long-term arterial response after sirolimus-eluting stent implantation. BACKGROUND Sirolimus-eluting stents are effective in inhibiting neointimal hyperplasia without affecting plaque volume behind the stent struts at six months. METHODS Serial quantitative intravascular ultrasound and computer-assisted grayscale value analysis over four years were performed in 23 event-free patients treated with sirolimus-eluting stents. RESULTS In the first two years, the mean plaque volume (155.5 +/- 42.8 mm(3) post-procedure and 156.8 +/- 57.7 mm(3) at two years, p = 0.86) and plaque compositional change expressed as mean percent hypoechogenic tissue of the plaque behind the stent struts (78.9 +/- 8.6% post-procedure and 78.2 +/- 8.9% at two years, p = 0.67) did not significantly change. However, significant plaque shrinking (change in plaque volume = -18.4 mm(3), p = 0.02) with an increase in plaque echogenicity (change in percent hypoechogenic tissue = -7.8%, p < 0.0001) was observed between two and four years. The mean neointimal volume increased over four years from 0 to 8.4 +/- 5.8 mm(3) (p < 0.0001). However, no further statistically significant change occurred between two and four years (7.0 +/- 6.7 mm(3) VS. 8.4 5.8 mm 3, p = 0.25). CONCLUSIONS Between two and four years after sirolimus-eluting stent implantation, peri-stent tissue shrank with a concomitant increase in echogenicity. These intravascular ultrasound findings suggest that late chronic artery responses may evolve for up to four years after sirolimus-eluting stent implantation. In addition, the fact that the neointima does not significantly change from two to four years may suggest that the biological phenomenon of a delayed healing response has begun to subside.