Repeat balloon angioplasty is a widely used therapeutic option for in-stent restenosis, but the optimal balloon inflation pressure has not yet been determined. We used angiography and intravascular ultrasound imaging to assess the mechanism and results of lumen enlargement at various inflation pressures. Thirteen consecutive patients with restenosis post-Palmaz-Schatz stent implantation were submitted to a four-step balloon angioplasty using increasing balloon pressure of 2, 4, 8, and >12 atm. As a global result, the lumen size was only 80% of that observed at stent implantation. Significant changes in angiographic minimal lumen diameter, minimal lumen cross-sectional area, and lumen volume were observed after each step except after the highest-pressure inflation. At low inflation pressure (<8 atm), the decrease in neointimal tissue and the stent over expansion explained the lumen enlargement, whereas after further high inflation pressure (>8 atm), only additional stent over expansion was observed. These results suggest that only moderate balloon inflation pressure (up to 12 atm) is needed for angioplasty of post-Palmaz-Schatz stent restenotic lesions.