This study was performed to compare the effects of rotational atherectomy (RA) plus balloon angioplasty (BA) with those of BA alone for treatment of diffuse in-stent restenosis. RA+BA or BA alone was performed in a consecutive, prospective (not randomized) manner in 81 patients with 81 diffuse in-stent restenotic lesions (lesion length > 10 mm): 36 patients underwent RA+BA, and 45 patients BA. Clinical recurrence was the primary end point of this study, and was defined as angina associated with objective evidence of myocardial ischemia on stress testing. Mean follow-up duration was 277 +/- 109 days. In the BA group, acute lumen gain after repeat intervention was significantly lower than that of the original stenting procedure (1.94 +/- 0.63 vs 2.37 +/- 0.51 mm, p <0.05). In the RA + BA group, however, acute lumen gain of repeat intervention was similar to that of the original stenting procedure (2.16 +/- 0.52 vs 2.26 +/- 0.66 mm). Clinical recurrence rate at 6 months follow-up was significantly lower in the RA+BA group than in the BA group (25% vs 47%, p <0.05). Clinical events (death, myocardial infarction, repeat intervention) occurred in 6.7% (3 of 45) of patients in the BA group, but in no patient in the RA+BA group during the follow-up period. The long-term angina-free survival rate was significantly higher in the RA+BA group than in the BA group (72% vs 49%, p = 0.02). In conclusion, RA+BA seems to be a more effective therapeutic modality than BA alone for treatment of diffuse in-stent restenosis.