The aim of this study was to determine the effect of opium on clinical and neuropsychological parameters in multiple sclerosis (MS) patients with substance dependency. A cross-sectional study was conducted on MS patients in Rafsanjan, Iran. Forty opium-addict MS patients (10 males and 30 females) aged between 18 and 50 years were compared with 40 MS patients with no addiction. Word-Pair Learning, Mini-Mental State Examination (MMSE), Wisconsin Card-Sorting Test (WCST), Depression, Anxiety, Expanded Disability Status Scale (EDSS), Fatigue, and the Multiple Sclerosis Functional Composite (MSFC) were measured and compared in the two groups. The comparison of two groups showed a significant increase trait anxiety (P < 0.001), fatigue (P = 0.009) and significant decrease in the executive function (P = 0.003), MMSE (P = 0.003), and working memory (P < 0.001) in addicted MS. It indicates the better efficiency of processing in the non-addicted MS patients. The MSFC z-score also was significantly higher in the non-addicted group (P < 0.001). The opium addiction has a negative impact on the clinical and neuropsychological outcome in MS patients.