In-stent restenosis (ISR), when treated with balloon angioplasty (PTCA) alone, has an angiographic recurrence rate of 30%-85%. Ablating the hypertrophic neointimal tissue prior to PTCA is an attractive alternative, yet the late outcomes of such treatment have not been fully determined. This multicenter case control study assessed the angiographic and clinical outcomes of 157 consecutive procedures in 146 patients with ISR at nine institutions treated with either PTCA alone (n = 64) or excimer laser assisted coronary angioplasty (ELCA, n = 93)) for ISR. Demographics were similar except more unstable angina at presentation in ELCA-treated patients (74.5% vs. 63.5%; P = 0.141). Lesions selected for ELCA were longer (16.8 +/- 11.2 mm vs. 11.2 +/- 8.6 mm; P < 0.001), more complex (ACC/AHA type C: 35.1% vs. 13.6%; P < 0.001), and with compromised antegrade flow (TIMI flow < 3: 18.9% vs. 4.5%; P = 0.008) compared to PTCA-treated patients. ELCA-treated patients had similar rate of procedural success [93 (98.9% vs. 62 (98.4%); P = 1.0] and major clinical complications [1 (1.1%) vs. 1 (1.6%); P = 1.0]. At 30 days, repeat target site coronary intervention was lower in ELCA-treated patients (1.1% vs. 6.4% in PTCA-treated patients; P = 0.158), but not significantly so. At 1 year, ELCA-treated patients had similar rate of major cardiac events (39.1% vs. 45.2%; P = 0.456) and target lesion revascularization (30.0% vs. 32.3%; P = 0.646). These data suggest that ELCA in patients with complex in-stent restenosis is as safe and effective as balloon angioplasty alone. Despite higher lesion complexity in ELCA-treated patients, no increase in event rates was observed. Future studies should evaluate the relative benefit of ELCA over PTCA alone for the prevention of symptom recurrence specifically in patients with complex in-stent restenosis.