•Alexithymia is a frequent manifestation in patients with multiple sclerosis.•The study included clinical, neuropsychological and radiological evaluations.•Alexithymia is associated with low empathy scores, and high fatigue and depression ratings.•Alexithymia is associated with low pallidal and thalamic volumes.•Alexithymia is associated with low deep white matter and corpus callosum volumes. Alexithymia is a personality construct that could occur in up to 53 % of patients with multiple sclerosis (MS). It entails difficulties in identifying and describing one’s feelings and an externally oriented thinking. The current work aims to assess the neural underpinnings of alexithymia in this population. Forty-five patients with MS filled in the Toronto Alexithymia Scale (n = 17 with high alexithymia and n = 28 with low alexithymia). Brain magnetic resonance imaging was obtained for each patient and a morphometry algorithm (MorphoBox) was applied to calculate regional brain volumes. All patients underwent a clinical and neuropsychological evaluation which included measures for anxiety, depression, fatigue, daytime sleepiness, and basic and social cognition. Compared to patients with low alexithymia, patients with high alexithymia had significantly higher fatigue and depression ratings, and lower empathy scores. In addition, they had lower volumes of corpus callosum, deep white matter, pallidum bilaterally, and left thalamus. In the whole cohort, alexithymia scores were inversely correlated with gray matter (thalamus and pallidum bilaterally) and white matter volumes (corpus callosum and bilateral deep white matter) after controlling for covariates (ps<0.05). This study offers insights on the neuropsychological and neural substrates of alexithymia in MS. The current findings are consistent with alexithymia reports in other clinical populations, and suggest an association between alexithymia and atrophy of thalami, pallidum, corpus callosum and deep white matter in MS. Further research is needed to enhance the understanding of alexithymia mechanisms in this clinical context.