We are aware of no studies of peri-stent disease progression or luminal compromise in saphenous vein graft (SVG) lesions. We used serial intravascular ultrasound (IVUS) to assess disease progression in peri-stent saphenous vein bypass graft reference segments. We studied 37 peri-stent SVG reference segments in 21 patients; 16 were proximal and 21 were distal to the stent. The same anatomic image slice was analyzed after the intervention and at follow-up; this site was 3.68 ± 2.22 mm from the stent edge. Graft age was 10.1 ± 5.4 years, and mean follow-up duration was 13 months (range 3 to 61). Overall, change in SVG area, change in lumen area, and change in plaque burden correlated with postintervention plaque burden (r = 0.448, p = 0.005; r = −0.584, p <0.001; and r = 0.507, p = 0.001, respectively). For the proximal edge, change in lumen area correlated with change in plaque area (r = −0.951, p <0.001), but not with change in SVG area (r = −0.337, p = 0.201). For the distal edge, change in lumen area correlated more strongly with change in plaque area (r = −0.982, p <0.001) than with change in SVG area (r = −0.624, p = 0.003). When peri-stent reference segments were divided into 2 groups according to postintervention plaque burden (>50% [n = 20] vs <50% [n = 17]), there was a greater decrease in lumen area (−1.12 ± 0.81 vs −0.33 ± 0.26 mm², p <0.001) and greater increases in SVG area (0.26 ± 0.29 vs 0.09 ± 0.09 mm², p = 0.027), plaque area (1.37 ± 0.96 vs 0.42 ± 0.30 mm², p <0.001), and plaque burden (8.2 ± 5.6% vs. 2.8 ± 1.6%, p <0.001) in segments with a plaque burden >50%. In conclusion, peri-stent reference segment SVG disease progression and lumen loss were more significant in segments with a greater postintervention plaque burden after implantation of a bare metal stent or drug-eluting stent.