Aims: To examine the effectiveness and safety of using a CAD/CAM–derived injection guide for botulinum neurotoxin block of the sphenopalatine ganglion for trigeminal neuralgia treatment. Methods: Ten patients with second-division trigeminal neuralgia who did not respond to submucosal administration of botulinum neurotoxin were enrolled in this study. The target point around the sphenopalatine fossa was determined after fusion of computed tomography data with a scan of a maxillary model using a software program for dental implant surgery. A CAD/CAM–derived injection guide was fabricated. The guide was affixed to the patient's maxilla, and a needle was inserted to an exactly analyzed depth. Subsequently, 50 units of botulinum neurotoxin were injected. Pain intensity evaluated using a visual analog scale and pain frequency were measured. Results: By using the guides, sphenopalatine ganglion block with botulinum toxin was performed 18 times without any complications. The visual analog scale score (8.1 ± 1.0) and pain frequency (19.4 ± 8.8 times/day) decreased (to 1.9 ± 1.4 and 4.9 ± 5.4 times/day, respectively) significantly (P .001). After 4 weeks, the mean subjective improvement achieved was 77.5% ± 13.8%, and all patients responded to treatment. Conclusion: Even without prior experience of sphenopalatine ganglion block, the CAD/CAM–derived guide enabled the accurate and safe administration of botulinum neurotoxin to the sphenopalatine ganglion for the treatment of trigeminal neuralgia. Keywords: botulinum neurotoxin therapy, computer-aided design/ computer-assisted manufacturing, sphenopalatine ganglion, surgical template, trigeminal neuralgia