Background & Aims: Substance abuse may have different effects on multiple sclerosis. Till now, studies on substance abuse and its correlation with psychopathology, type and severity of multiple sclerosis are limited. We conducted this study to evaluate the psychopathology of patients with multiple sclerosis with and without substance abuse. Methods: In this case-control, cross-sectional study performed in 2012, 125 patients with multiple sclerosis in Kerman were enrolled. From all, 100 patients did not have substance abuse and 25 ones had substance abuse. In each group, the Millon Clinical Multiaxial Inventory-III (MCMI-III) test was done by patient and the patients’ Expanded Disability Status Scale (EDSS) were determined. We used DSM IVTR criteria to diagnose substance abuse. Results: The frequency of obsessive convulsive disorder (OCD) was significantly higher in patients without substance abuse and paranoia, delusional, and sadistic were significantly higher in substance abuse group (P<0.05). The achieved Expanded Disability Status Scale (EDSS) was significantly higher in substance abusers. Also, the type of multiple sclerosis was different between the two groups. The relapsing-remitting type was higher in the group without substance abuse and the progressive-relapsing type was higher in the group with substance abuse. Conclusion: Psychiatric disorders were seen in both groups. Substance abuse had correlation with psychopathology, type and severity of multiple sclerosis.