Disorders involving regulation of affect commonly occur in multiple sclerosis (MS). These include various clinical presentations with inconsistent definitions that lead to many nomenclatures. In order to simplify the clinical approach to dysregulation of affect (DyA) a phenomenological definition was applied that unifies and combines the current classifications. Accordingly, the prevalence of DyA was determined in MS patients and comorbidity was evaluated with psychiatric disorders. Using the Structured Clinical Interview for DSM-III-R (SCID), 651 consecutive MS patients were assessed (474 female, 177 male, mean age 43.6 years, mean disease duration 11.5 years) and it was found that the prevalence of DyA was 6.5% (n = 42). In 14 patients (33.3% of DyA patients) there was no associated psychiatric comorbidity, while in 28 patients (66.6%) there was comorbid psychopathology; 12 had been suffering from psychosis (28.6%), eight from mood disorders (19%), six from cognitive decline (14.3%) and two from personality disorder (4.7%). In 15 patients (35.7%) the DyA was ego-dystonic and in 27 patients (64.3%) the symptoms of DyA were ego-syntonic. All patients with comorbid psychosis had ego-syntonic DyA. In 14.3% of patients the DyA symptomatology preceded the appearance of MS. It is concluded that the new phenomenological definition of DyA aids in distinguishing this symptom from other psychopathologies and can serve as a tool for neurologists in defining this unique entity.