Introduction Image-guided robotic radiosurgery is an emerging minimally-invasive treatment option for trigeminal neuralgia (TN). Our group has treated 560 cases up to date, and report here the clinical outcomes of 387 treatments with three years follow-up. This study represents the largest single-center experience on CyberKnife radiosurgery for the treatment of TN so far reported. Methods CyberKnife radiosurgery treatment was offered to patients with drug-resistant TN, after the failure of other treatments or refusal of invasive procedures. A second treatment was offered to patients with a poor response after the first treatment or with recurrent pain. Treatment protocol required the non-isocentric delivery of 60 Gy prescribed to the 80% isodose to a 6 mm retrogasserian segment of the affected trigeminal nerve. Retreatments typically received 45 Gy, again prescribed to the 80% isodose. The final plan was developed accordingly to individual anatomy and dose distribution over the trigeminal nerve, gasserian ganglion, and brainstem. Clinical outcomes such as pain control and hypoesthesia/numbness have been evaluated after 6, 12, 24, and 36 months. Results Our group has treated 527 patients with Cyberknife radiosurgery at Centro Diagnostico Italiano (CDI), Milan, Italy, during the last decade. A minimum follow-up of six months was available on 496 patients. These patients received 560 treatments: 435 patients (87.7%) had a single treatment, 60 patients (12.1%) had two treatments, and one patient (0.2%) had five treatments (two on the right side, three on the left side). Twenty four patients had multiple sclerosis (4.8%). Four hundred and forty-three patients (84%) received the treatment without previous procedures, while 84 patients (16%) underwent radiosurgery after the failure of other treatments. A neurovascular conflict was identified in 59% of the patients. Three hundred and forty-three patients (receiving a total of 387 treatments) had a minimum of 36 months follow up. Pain relief rate at 6, 12, 18, 24, 30 and 36 months was respectively 92, 87, 87, 82, 78 and 76%. Forty-four patients out of 343 (12.8%) required a second treatment during the observed period. At 36 months post-treatment, 21 patients (6,1%) reported the presence of bothering facial hypoesthesia. Eighteen patients out of 21 (85.7%) developed this complication after a repeated treatment. Conclusions Frameless image-guided robotic radiosurgery in experienced hands is a safe and effective procedure for the treatment of TN, providing excellent pain control rates in the absence of major neurological complications. Repeated treatments due to recurrent pain are associated with restored pain control but at the price of a higher rate of sensory complications.