Objective: To investigate whether $ømega$-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. Design: Multicenter, randomized, double-blind, placebocontrolled clinical trial conducted from 2004 to 2008. Setting: Thirteen public neurology departments in Norway. Participants: Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to $ømega$-3 fatty acids (n=46) or placebo capsules (n=46). Interventions: Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 $μ$g of interferon beta-1a 3 times per week for another 18 months. Main Outcome Measure: The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. Results : The cumulative number of gadoliniumenhancing MRI lesions during the first 6 months were similar in the $ømega$-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P =.09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P =.54) or 24 (median difference, 0; 95% CI, 0 to 0; P =.72) months. The proportion of patients without disability progression was 70% in both groups ( P textgreater .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in $ømega$-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P textless .001) in the patients treated with $ømega$-3 fatty acids compared with the placebo group. Conclusion: No beneficial effects on disease activity were detected from $ømega$-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. Trial Registration: clinicaltrials.gov Identifier:NCT00360906. ©2012 American Medical Association. All rights reserved.