Summary Introduction Large vascular lesions in the orofacial region are often very difficult to remove. In the 1990s, the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser emerged as a new and effective mode of treatment for vascular lesions. The purpose of this paper was to determine its effectiveness and safety for the treatment of large vascular lesions in the orofacial region. Patients and methods A prospective study was conducted in which 28 patients with large vascular lesions (their surface diameters being more than 3 × 3 cm) in the orofacial region were treated with the Nd:YAG laser by photocoagulation (PhC). Four different modalities of treatment were used: simple transmucosal PhC, transmucosal PhC with the use of compression, simple intralesional PhC, and ultrasound guided intralesional PhC. Follow up was conducted in all of the cases, time until complete healing was recorded, as were postoperative complications. Results In all of the patients undergoing transmucosal PhC (simple or with the use of compression), tissue sloughing occured within 1–3 days, and the time until complete healing was 3–5 weeks. In patients undergoing intralesional PhC (simple or ultrasound guided), swelling was present for 1 week. There were no cases of inadvertent bleeding. Nine patients required two or more sessions of PhC. Three patients required a corrective surgical procedure as the final step. Two patients required prolonged intubation and one patient a temporary tracheostomy, all due to oedema. Two patients developed a local intraoral infection, which was controlled with broad-spectrum oral antibiotics. Conclusion If used properly, the Nd:YAG laser is a safe and effective tool for the treatment of large vascular lesions.