Percutaneous laser ablation (PLA) is a proposed therapeutic procedure for the management of benign thyroid nodules. However, long-term results are unknown. The aim of this study was to evaluate retrospectively the safety and effects of PLA treatment in patients with benign nonfunctioning thyroid nodules in a 3-year follow-up. One hundred twenty-two patients (95 women and 27 men; age 52.2 ± 12.3 years) with benign cold thyroid solitary nodules or a dominant nodule within a normo-functioning multinodular goiter (volume range: 2.6-86.4 mL) underwent thermal Nd:YAG laser ablation of thyroid nodular tissue by 1-4 optical fibers positioned into the tissue by 21-gauge needles under ultrasound real-time assistance. The setting was an interventional suite and outpatient endocrine clinics in a community hospital in Italy. Nodule volume, ablation volume, side effects, serum thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine (fT4), thyroglobulin (Tg), anti-Tg, anti-thyroperoxidase antibodies, symptoms, and cosmetic signs were recorded. Data are mean ± standard deviation. Energy delivered was 8522 ± 5365 J with an output power of 3.1 ± 0.5 W. Three years after PLA, nodule volume decreased from 23.1 ± 21.3 to 12.5 ± 18.8 mL (-47.8% ± 33.1% of initial volume, p ≤ 0.001). At day 1, TSH and fT4 values significantly changed (time 0 vs. day 1: TSH = 1.16 ± 1.06 vs. 0.62 ± 0.81 μU/mL, p ≤ 0.001; fT4 = 11.68 ± 1.88 vs. 13.20 ± 3.32 pg/mL, p ≤ 0.01) and normalized within 1 month. No change in free triiodothyronine, thyroperoxidase antibodies, and Tg antibodies values was observed. Symptoms improved in 89 patients (73.0%), were unchanged in 28 (22.9%), and worsened in 5 (4.1%). Cosmetic signs improved in 87 patients (71.3%), were unchanged in 29 (23.8%), and worsened in 6 (4.9%). In 11 patients (9%), nodules regrew above baseline. Two patients (1.6%) experienced delayed (12-24 hours) laryngeal dysfunction with vocal cord motility recovery after 6-10 weeks. Two patients (1.6%) became hypothyroid and two patients (1.6%) hyperthyroid after PLA. After 3 years, the PLA technique achieved shrinkage of about 50% of the initial volume in a wide size range of benign cold thyroid nodules, with an improvement in local symptoms and signs. Side effects and failures were few although not negligible. PLA may be a new option for the management of benign cold thyroid nodules. Long-term controlled studies are required to establish the eligibility of patients for routine PLA.