Drug-eluting stents (DESs) may represent a simple, effective treatment for in-stent restenosis (ISR); however, the underexpansion of stents is a significant cause of target vessel failure. It was hypothesized that high-pressure postdilatation would be necessary to optimize DES expansion and minimize the risk for restenosis when treating patients with ISR. Fifteen patients with diffuse ISR were treated by predilatation (including cutting balloons), DES deployment, and high-pressure postdilatation, with the measurement of luminal and stent dimensions by intravascular ultrasound after each intervention. After initial deployment, DES underexpansion was present in 10 of 15 patients (66%); after high-pressure postdilatation, there was a significant increase in luminal dimensions, including minimum luminal area (4.3 +/- 0.3 to 5.6 +/- 0.4 mm(2), p <0.001) and a doubling in the proportion of patients with optimal stent expansion. At long-term follow-up (median 11 months), target lesion revascularization occurred in 1 patient (7%) because of edge restenosis; there was no restenosis within the DES.