Aim: We aimed to determine the efficacy and safety of etodolac, in acute migraine attacks in comparison with paracetamol (acetaminophen). Methods: We designed a randomized, double-blind, crossover phase III clinical trial for patients diagnosed with migraine for at least 1year, according to ICHD-II criteria. Two hundred and twenty-nine adult patients having 2 to 8 attacks monthly from 17 centers were included. The patients were instructed to use 3 attack treatment packages consisting of 1,000mg paracetamol, 400mg etodolac, and 800mg etodolac on 3 migraine attacks of moderatesevere intensity each in a 3-month treatment period, interchangeably. Results: Any pain medication was used in 1,570 migraine attacks while study treatments were used in 1,047 attacks. The results for 1,000mg paracetamol, 400 mg etodolac, and 800 mg etodolac were as follows: response of headache at 2hours 44.9%, 48.3% and 46.1%; pain-free at 2hours 19.2%, 19.3% and 24.1%; sustained pain-free from 2 to 24hours 34.3%, 38.3% and 41.1%; relapse rates in 2 to 24hours 7.3%, 14.3% and 9.7%. There were no statistically significant differences between the groups regarding the headache response, pain-free, sustained pain-free, and relapse rates. Nausea, vomiting, phonophobia, or photophobia decreased similarly in all groups within 24hours of treatment administration. Drug-related adverse events were noted in 8 patients with 1,000mg paracetamol, in 9 patients with 400mg etodolac and in 9 patients for 800mg etodolac during the study. Comment: Our study showed that etodolac is a safe and effective alternative in acute migraine treatment and showed comparable efficacy to paracetamol 1,000mg. Etodolac may be considered as an alternative option for acute treatment of migraine.