Background <p>Trigeminal neuralgia associated with multiple sclerosis (MS-TN) is frequently refractory to medical and procedural therapy, particularly in the absence of neurovascular compression. Surgical options are limited when microvascular decompression is not appropriate. We report a salvage surgical approach combining internal neurolysis and targeted proximal trigeminal root glycerol injection for refractory MS-related trigeminal neuralgia.</p> Case presentation <p>A 50-year-old woman with relapsing–remitting multiple sclerosis presented with medically refractory right-sided trigeminal neuralgia predominantly involving the V2/V3 distributions. She had previously failed optimisation of pharmacotherapy, two percutaneous retrogasserian glycerol rhizotomies, and Gamma Knife radiosurgery performed within the preceding year. Posterior fossa exploration via a retrosigmoid approach demonstrated no neurovascular conflict. Internal neurolysis (nerve combing) was therefore performed and supplemented with targeted glycerol delivery to the proximal cisternal segment of the trigeminal root adjacent to the radiologically relevant demyelinating lesion. Postoperatively, the patient experienced immediate improvement in facial pain with preservation of trigeminal sensation and no new neurological deficits. Her early postoperative course was complicated by a wound infection requiring surgical washout and antibiotic therapy. At 43-month follow-up, she remained free of ipsilateral trigeminal neuralgia with substantially reduced medication requirements. She later developed contralateral facial pain controlled with low-dose carbamazepine without recurrence on the operated side.</p> Conclusion <p>This report describes, to our knowledge, the first published case of combined internal neurolysis and targeted proximal trigeminal root glycerol injection for refractory multiple sclerosis–related trigeminal neuralgia. In this highly selected case, durable ipsilateral pain control was observed. However, causal interpretation is limited by the single-case design, the combined nature of the intervention, and the potential delayed effects of prior radiosurgery. This approach should therefore be regarded as hypothesis-generating rather than practice-defining, but may merit further study as a salvage strategy in selected patients without neurovascular compression after failure of medical, percutaneous, and radiosurgical treatments.</p>