A high co-morbidity between multiple sclerosis (MS) and migraine has been reported, especially in young female patients affected by a relapsing-remitting (RR) course of MS. In this study, we aimed to elucidate the determinants of the severity of comorbid migraine in MS. Demographic, clinical and psychometric variables were collected from a cohort of 205 RR-MS patients regularly attending to an Italian outpatient MS Centre. Of them, 102 (49.8 %) were diagnosed as affected by comorbid migraine. About one-third of MS patients with comorbid migraine have asked the attending neurologist a specific anti-migraine treatment. Despite this, only few MS patients (10.8 %) reported a prior use of prophylactic drugs, and even fewer (2.9 %) took triptans as pain killers; these proportions were significantly lower when compared with those of a control group of 63 migraineurs subjects without MS (p < 0.0001 for both comparison). Factors associated with a moderate or severe disability (MIDAS grades III or IV) due to comorbid migraine in MS patients were the depressive state (OR = 4.294; p = 0.001), the anxiety trait (OR = 5.786; p = 0.004) and an ongoing IFNB treatment (OR = 2.337; p = 0.028). Likewise, depression (OR = 3.453; p = 0.048) and anxiety (OR = 4.582; p = 0.014) were both independent predictors for having a MIDAS grades of III or IV also in migraineurs subjects without MS. Investigating the determinants of migraine severity may allow a better management of MS patients with comorbid migraine. In these patients, a tailored therapeutic approach is warranted to improve their quality of life and reduce the burden of these two chronic and disabling conditions.