PurposeMultiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are two major demyelinating diseases affecting the central nervous system (CNS). The objective of this study is to evaluate the prevalence of pontine trigeminal nerve lesions in patients diagnosed with MS and NMOSD using MRI. MethodsThis retrospective study included patients diagnosed with MS or NMOSD between July 2018 and July 2023. MS patients were clinically diagnosed using the 2017 McDonald criteria, while NMOSD patients were those who met the 2015 International Panel for NMO Diagnosis (IPND) criteria and were positive for Aquaporin-4 Antibody (AQP4-Ab). ResultsThe study included a total of 90 patients, with 45 diagnosed with MS and another 45 with NMOSD. Pontine trigeminal nerve lesions were observed in both MS and NMOSD, but were more prevalent in MS patients (20 % vs. 2 %, p = 0.008). Root entry zone (REZ) lesions were found in 4 of 45 MS patients, accounting for 9 % (95 % CI: 3 %–17 %), and were absent in the NMOSD group; however, there was no significant difference between the two groups (p = 0.12). Of the MS patients with pontine trigeminal nerve lesions, 6 out of 9 (63 %; 95 % CI, 36 %–98 %) exhibited bilateral lesions, which was significantly more prevalent compared to the NMOSD group (13 % vs. 0 %, p = 0.03). ConclusionsThe presence of pontine trigeminal nerve lesions, particularly when bilateral, are significantly more prevalent in MS patients than in those with NMOSD, suggesting their utility as a distinctive marker and potential diagnostic indicator specifically for MS.