BACKGROUND Multiple sclerosis (MS) is a chronic autoimmune disease that can deteriorate cognitive function in at least 50% of patients even in the early stages. OBJECTIVE We conducted a three-arm parallel study with balanced randomization to evaluate the effect of various disease-modifying therapies (DMTs) on cognitive function in MS. METHODS Ninety newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran, were enrolled into this study between 2006 and 2009. They were randomly categorized into three DMT groups; Avonex, Rebif and Betaferon. Cognition status was assessed in MS patients at baseline and 12 months after treatment with DMTs using the 5 tests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). RESULTS The Symbol Digit Modalities Test scores improved in all groups at 12 month vs. baseline (Avonex: 34.50 vs. 38.95, p=0.011; Rebif: 35.30 vs. 40.13, p=0.001; Betaferon: 26.18 vs. 29.32, p=0.029). The Selective Reminding Test (SRT)-Total, the 10/36-Delay, and the Paced Auditory Serial Addition Test-Easy were improved in Avonex and Rebif but not in Betaferon group. The SRT-Delay and Word List Generation were improved only in the Avonex group. There was no significant difference in other components of the BRB-N among these three treatment groups. CONCLUSIONS Different types of DMTs may improve some aspects of cognitive function in patients with MS. Treatment with Avonex and Rebif (Interferon beta-1a preparations) were more helpful in resolving the cognitive impairments in MS patients compared to Betaferon (Interferon beta-1b) as investigated in this study.