We aimed to compare the therapeutic effect of Avonex (Av), Betaferon (Be) & Rebif (Re) on the Expanded Disability Status Scale (EDSS) in Multiple Sclerosis (MS). Ninety patients referring to Farshchian Hospital were entered in this study. The patients were divided into three equal groups: group 1 received Av, group 2 received Re and group 3 received Be, and after 24 months, comparison was done by calculating primary and final EDSS and the relapse rate. For comparison of the primary and final EDSS in each group, the relapse rate between the groups and side effects between the drugs, the paired samples t.test, the One-Way ANOVA test and the Pearson- chi-square were used. Average age was 31.11 ± 8.62 years, 80% being female. Comparison of the average primary and final EDSS using the paired samples t.test showed a significant statistical difference (P < 0.05). Motor and visual disturbances (respectively 68.3% and 60.3%) were the most common signs and relapsing- remitting form was the most common form (42.1%). The average EDSS change of groups Av, Be and Re was respectively, 1.28 (29.76%), 1.30(24.30%) and 1.26 (26.63%), showing no significant statistical difference in reducing EDSS. Groups Av and Be, showed no significant statistical difference in the average relapse rate before and after treatment, but in group Re there was a significant difference (P < 0.05). Treatment with these drugs reduces motor disability, with no significant difference between them. Also in comparison, Re has a greater effect in reducing the relapse rate, but again with no significant statistical difference among them.