Background Recurrent restenosis may occur after drug-eluting stent implantation for in-stent restenosis (ISR) of bare metal stents (BMSs), especially in areas involving drug-eluting stent gaps. Methods To investigate the details of neointimal progression and luminal narrowing after the treatment of ISR using sirolimus-eluting stents (SESs), serial intravascular ultrasound analysis was performed in 65 patients with ISR at postintervention and at 6-month follow-up. The total stented segment was categorized into 3 compartments: new SES (N), new SES and old BMS overlap (N/O), and old BMS (O). In each of the 190 compartments, serial intravascular ultrasound parameters were analyzed at the cross section of the maximum change in neointimal area (Δneointimal area) from postintervention to follow-up or the minimum lumen area at follow-up if Δneointimal area was 0. Minimum lumen area in each compartment was also investigated serially. Results At postintervention, lumen area was the smallest in compartment N/O (N 5.8 ± 1.5, N/O 5.1 ± 1.3, O 6.0 ± 1.4 mm 2, P = .005). Not only the average of maximum Δneointimal area (N 0.2 ± 0.4, N/O 0.2 ± 0.4, O 0.8 ± 1.0 mm 2, P < .0001) but also the frequency of minimum lumen area decreasing from ≥4.0 mm 2 at postintervention to <4.0 mm 2 at follow-up (N 4.0%, N/O 5.1%, O 23.5%, P = .012) was the largest in compartment O. Conclusions Neointimal progression and consequent luminal narrowing tend to occur where BMS is uncovered with SES in treatment of ISR, even in the absence of an obvious stenosis at postintervention.