In-stent restenosis remains a clinical therapeutic challenge. Rotational atherectomy (RA) is an attractive treatment option as it may cause less vascular injury than balloon angioplasty (BA) and, therefore, limit further neointimal response. In an animal model of coronary in-stent restenosis, thermal injury and stenting created neointima (old NI). The treatment of in-stent restenosis with either BA (n = 9) or RA (n = 11) also generated neointima (new NI). The average areas (mm2) of old NI in the BA and RA groups were similar (3.77 +/- 0.40 vs. 3.67 +/- 0.53; P = 0.32). However, new NI formed after treatment of in-stent restenosis was significantly less in the RA as compared to the BA group (0.33 +/- 0.12 vs. 0.73 +/- 36, P < 0.01). In this porcine coronary artery model of in-stent restenosis, treatment with rotational atherectomy resulted in significantly less recurrent neointimal hyperplasia than balloon angioplasty. This animal study, thus, provides a rationale for the clinical use of rotablation in the treatment of in-stent restenosis.