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Background: Migraine is a common cause of disability and loss of work. Migraine attacks are a complex brain event that unfolds over hours to days, in a recurrentmanner.A high frequency of migraine attacks can lead to frequent intake of acute medication, which may result in medication-overuse headache. Therefore, prophylaxis of migraine is justified as an important goal. Objective: To study and compare the clinical effectiveness and side effects of various migraine prophylactic drugs. Materials and methods: The patients fulfilling the inclusion and exclusion criteria were enrolled into this randomized, single blind study carried out in the patients visiting the Neurology OPD of Gauhati Medical College and Hospital, Guwahati from November 2022 to October 2023and were prescribed one of the following migraine prophylactic drugs-propranolol, amitriptyline, divalproex and desvenlafaxine. The initial four weeks were used for drug dose titration to minimum effective or maximum tolerable dosage and after optimal dose titration, the following 12 weeks were used to assess the efficacy of the drugs. MIDAS(Migraine Disability Assessment Score) questionnaire and Headache Impact Test-6(HIT-6) along with drug diary were used to assess the pre and post drug intervention quality of life which will help in assessing the efficacy of the drugs being used. Results: The study had a total of 100 patients with a median age of 28 years, with most of the patients presenting in the third decade of life. The male to female ratio was 1:2.3. The mean MIDAS scores at day 0 and at 3 months for the propranolol group were 18.9 and 7.20; for amitriptyline group it was 16.43 and 8.21, for divalproex it was 16.28 and 9.77, and for desvenlafaxine it was 17.5 and 8.5 respectively. The mean HIT-6 scores at day 0 and at 3 months for the propranolol group were 54.52 and 41.60; for theamitriptyline group it was 52.85 and 45.33, for divalproex it was 53.2 and 44.71, and for desvenlafaxine it was 52.18 and 42.26 respectively. All the 4 groups had comparable reduction in headache burden and number of headache days permonth based on mean MIDAS and HIT-6 scores. Conclusion: All the 4 groups had comparable reduction in headache burden and number of headache days per month based on mean MIDAS and HIT-6 scores and on t-test there was no significant difference in the mean scores between the groups indicating similar efficacy of the drugs used in the study. There were no adverse or side effects noted in any of the patients. [ABSTRACT FROM AUTHOR]