Background <p>Previous studies on Benign Multiple Sclerosis (BMS) relied mostly on the Expanded Disability Status Scale (EDSS) for classification. In addition, the underlying mechanisms of BMS are not yet fully understood. Therefore, we analyzed the frequency of BMS when parameters beyond EDSS are included, and BMS neuroimaging correlates.</p> Methods <p>BMS (EDSS ≤ 3.0 after 10 years of onset) and traditional MS (EDSS &gt; 3.0 after the same period) individuals underwent assessment of physical disability, fatigue, depression, and cognition. BMS were further classified according to a stringent EDSS-based criteria (EDSS ≤ 2.0 after 15 years of onset) and as fully benign (no fatigue, depression or cognitive deficit). We quantified lesions in four locations for dissemination in space (DIS). Logistic regression was employed to analyze clinical/demographic and neuroimaging predictors of BMS.</p> Results <p>Individuals with traditional MS (<i>n</i> = 23) and BMS (<i>n</i> = 30) had similar frequency of depression. Thirteen (43.3%) BMS individuals had no fatigue, depression or cognitive deficit. Lesions at each DIS location were similarly distributed across groups, except for the spinal cord which was lower in BMS (<i>p</i> = 0.024). After logistic regression, education (OR = 0.839, 95%CI 0.716–0.984) and spinal cord lesions (OR = 1.364, 95%CI 1.054–1.765) were associated with BMS.</p> Conclusions <p>Individuals with the EDSS-based classification of BMS show a similar frequency of depression compared to traditional RRMS, underscoring the need of a broader definition of BMS. Higher education and less spinal cord lesions are associated with the BMS status.</p>