BACKGROUND This study aimed to investigate performance, effectiveness, and safety of excimer laser atherectomy for the treatment of complex lower limb artery disease in a real-world setting. METHODS In our prospective, multicenter registry, consecutive patients with complex lower limb lesions underwent excimer laser atherectomy with optional standard balloon angioplasty, paclitaxel-coated balloon angioplasty, and bailout stenting. Primary outcome was technical success. Secondary outcomes were device performance of the excimer laser system, freedom from target lesion revascularization (TLR), peri-procedural complications, and amputation-free survival in patients with critical limb ischemia (CLI). RESULTS A total of 294 patients were enrolled at 14 European centers (mean lesion length 109±103 mm, total occlusions 56.8% [167 of 294 lesions], CLI 47.3% [132 of 279 patients]. Adjuvant balloon angioplasty was conducted in 283 (96.3%), and complementary stent implantation in 98 patients (33.3%). Technical success was achieved in 95.3% of patients. Increasing lesion length was associated with decreased laser atherectomy performance (odds ratio [OR] per 10 mm: 0.94 [95% confidence interval [CI] 0.90 to 0.99], P=0.01). A total of 66 patients (22.4%) completed the 12-month follow-up. Freedom from TLR was 83.5% (95% CI: 74.9 to 92.1) at 12 months. Chronic total occlusions were associated with more TLR (OR 5.03 [95% CI: 1.01 to 25.1], P=0.049). Amputation -free survival in patients with CLI was 93.1% (95% CI: 83.9 to 100). CONCLUSIONS Excimer laser atherectomy substantially contributed to technical success of endovascular treatment of complex infra-inguinal lesions. Freedom from 12-month TLR was reasonable.