BACKGROUND Restenosis occurs after 30% to 50% of transcatheter coronary procedures; however, the natural history and pathophysiology of restenosis are still incompletely understood. RESULTS Serial (postintervention and follow-up) intravascular ultrasound imaging was used to study 212 native coronary lesions in 209 patients after percutaneous transluminal coronary angioplasty, directional coronary atherectomy, rotational atherectomy, or excimer laser angioplasty. The external elastic membrane (EEM) and lumen cross-sectional areas (CSA) were measured; plaque plus media (P+M) CSA was calculated as EEM minus lumen CSA. The anatomic slice selected for serial analysis had an axial location within the target lesion at the smallest follow-up lumen CSA. At follow-up, 73% of the decrease in lumen (from 6.6+/-2.5 to 4.0+/-3.7 mm2, P<.0001) was due to a decrease in EEM (from 20.1+/-6.4 to 18.2+/-6.4 mm2, P<.0001); 27% was due to an increase in P+M (from 13.5+/-5.5 to 14.2+/-5.4 mm2, P<.0001). Delta Lumen CSA correlated more strongly with delta EEM CSA (r=.751, P<.0001) than with delta P+M CSA (r=.284, P<.0001). Delta EEM was bidirectional; 47 lesions (22%) showed an increase in EEM. Despite a greater increase in P+M (1.5+/-2.5 versus 0.5+/-2.0 mm2, P=.0009), lesions exhibiting an increase in EEM had (1) no change in lumen (-0.1+/-3.3 versus 3.6+/-2.3 mm2, P<.0001), (2) a reduced restenosis rate (26% versus 62%, P<.0001), and (3) a 49% frequency of late lumen gain (versus 1%, P<.0001) compared with lesions with no increase in EEM. CONCLUSIONS Restenosis appears to be determined primarily by the direction and magnitude of vessel wall remodeling (delta EEM). An increase in EEM is adaptive, whereas a decrease in EEM contributes to restenosis.