Patients with acute myocardial infarction (AMI) with thrombus-laden lesions constitute a revascularization challenge. Thrombus and atherosclerotic plaque absorb laser energy; thus, we studied the safety and efficacy of excimer laser in AMI. In a multicenter trial, 151 patients with AMI underwent excimer laser angioplasty. Baseline left ventricular ejection fraction was 44 +/- 13%, and 13% of patients were in cardiogenic shock. A saphenous vein graft was the target vessel in 21%. Quantitative coronary angiography and statistical analysis were performed by independent core laboratories. A 95% device success, 97% angiographic success, and 91% overall procedural success rate were recorded. Maximal laser gain was achieved in lesions with extensive thrombus burden (p <0.03 vs small burden). Thrombolysis In Myocardial Infarction (TIMI) trial flow increased significantly by laser: 1.2 +/- 1.1 to 2.8 +/- 0.5 (p <0.001), reaching a final 3.0 +/- 0.2 (p <0.001 vs baseline). Minimal luminal diameter increased by laser from 0.5 +/- 0.5 to 1.6 +/- 0.5 mm (mean +/- SD, p <0.001), followed by 2.7 +/- 0.6 mm after stenting (p <0.001 vs baseline and vs after laser). Laser decreased target stenosis from 83 +/- 17% to 52 +/- 15% (mean +/- SD, p <0.001 vs baseline), followed by 20 +/- 16% after stenting (p <0.001 vs baseline and vs after laser). Six patients (4%) died, each presented with cardiogenic shock. Complications included perforation (0.6%), dissection (5% major, 3% minor), acute closure (0.6%), distal embolization (2%), and bleeding (3%). In a multivariant regression model, absence of cardiogenic shock was a significant factor affecting procedural success. Thus, in the setting of AMI, gaining maximal thrombus dissolution in lesions with extensive thrombus burden, combined with a considerable increase in minimal luminal diameter and restoration of anterograde TIMI flow, support successful debulking by excimer laser. The presence of thrombus does not adversely affect procedural success; however, cardiogenic shock remains a predictor of major adverse events during hospitalization.