Objective: To estimate effectiveness of presumptive doxycycline or azithromycin treatment in preventing progression of Acute Febrile Illness to Acute Encephalitis Syndrome in Gorakhpur. Study Design: Prospective cohort study. Study Setting: Primary healthcare centers and Community healthcare centers of Gorakhpur district, Uttar Pradesh. Participants: Children aged 1 year to less than 15 years with fever of 3 days to less than 15 days duration attending three selected peripheral health facilities in Gorakhpur during August to October, 2018. Procedure: 35 medical officers in three selected Primary Healthcare Centers/Community Healthcare centers were sensitized on the treatment strategy. After sensitization, study participants were enrolled and information about prescription of doxycycline or azithromycin was collected. Participants were telephonically followed-up to know their progression status from AFI to AES. Main outcome measure: Incidence of acute encephalitis syndrome among acute failure illness patients who received presumptive doxycycline or azithromycin treatment and those who did not receive this treatment. Results: Of the enrolled 930 AFI patients, 801 (86%) were prescribed doxycycline or azithromycin and 725 (78%) could be telephonically followed-up. Progression to acute encephalitis syndrome was seen in 6 of the 621 patients who received presumptive treatment, and 5 of the 104 who did not receive the treatment. The relative risk of developing acute encephalitis syndrome among acute febrile illness patients who were prescribed presumptive treatment with doxycycline or azithromycin was 0.20 (95% Cl: 0.06–0.65). The effectiveness of presumptive treatment with doxycycline or azithromycin strategy was 79.9% (95% CI: 35.4–94). Conclusion: PDA treatment to children presenting with fever in peripheral health facilities of the study blocks in Gorakhpur during August-November, 2018 had good effectiveness in preventing progression of acute febrile illness to acute encephalitis syndrome. © 2020, Indian Academy of Pediatrics.