Objectives: To assess the efficacy, tolerability and clinical outcome of high dose IV Vitamin C administration in patients with Acute respiratory distress syndrome (ARDS). Design: A prospective, randomized, controlled, open-label study. Setting: Intensive Care Unit of Embaba-Chest Hospital, Cairo, Egypt. Patients: Forty clinically and radiologically diagnosed cases of eligible ARDS patients were randomized to either, Group 1 (Control); 20 patients received conventional ARDS management, or Group 2 (Test); 20 ARDS patients received IV Vitamin C 10 g on two divided doses, both for 10 days. Interventions: Vitamin C, Interleukin 8 (IL8) and nuclear factor erythroid 2–related factor 2 (NRf2) levels together with PaO2/FiO2 were all measured for both groups at baseline and after 10 days. Main Results: Groups were comparable at baseline. After 10 days of Vitamin C administration, a significant increase (P<0.001) in levels of Vitamin C, NRf2 and PaO2/FiO2 together with a significant decrease (P<0.001) in IL8 was noted in test versus control group. Number of patients weaned off mechanical ventilation MV was significantly higher in test versus control groups (15 versus 6, p=0.004, respectively). Survival and occurrence of side effects were comparable between groups. Conclusions: Administration of 10 g IV Vitamin C in 2 divided doses daily for 10 days in ARDS patients improved lung functions, pulmonary oxygenation, oxidative stress and inflammatory markers and weaning off MV and reduced IL8 levels. Vitamin C was tolerable with no significant side effects or drug interactions reported throughout the 10 days-treatment. (Clinicaltrials.gov Registration number: NCT03780933)