Background: Omega-3 polyunsaturated fatty acids (PUFA) have beneficial effects on both specific and non-specific inflammatory reactions. The aim of this study was to evaluate the effect of dietary supplementation with fish oil in migraine prevention.Methods: A 12-week, randomized, single-blind clinical trial was conducted from October 2008 to June 2009. A total of 67 patients (52 women, 15 men) with migraine headache were randomly allocated to 2 groups. In the first group, 38 patients (30 females with a mean age of 35 ± 9 year) received 400 mg/day sodium valproate. In the second group, 29 patients (22 females with a mean age of 36 ± 9 years) received sodium valproate 400 mg daily plus fish oil supplementation (180 mg). Response to the treatment was assessed at 0, 1, 2, and 3 months after start of the therapy.Results: A significant decrease in duration, monthly frequency, and severity of headache after month 1, 2, and 3 in comparison with month 0 occurred in both groups. There was a significant reduction in headache severity (P = 0.046) and frequency (P = 0.044) in the group with fish oil supplementation after month 1 in comparison with sodium valproate alone. In contrast, there was no significant difference between two treatment groups in duration of the headache after month 1. Mean intensity, mean duration and mean frequency of the attacks after month 2 and 3 were not significantly different between the two groups.Conclusion: This study demonstrated that sodium valproate plus fish oil supplementation significantly reduces migraine headache more than sodium valproate alone but only at the beginning of the treatment.