Background: Although FiO 2-determined PEEP is the standard in ARDS management, previous trials failed to show agreement on outcomes. Based on heterogeneous ARDS pathology, we evaluated the effect of LUS-determined PEEP on oxygenation and outcomes. Methods: In this prospective, controlled trial, we randomly assigned 60 patients into LUSdetermined PEEP (group l) and FiO 2-determined PEEP (group II). LUS-determined PEEP was based on LUS aeration score. Primary outcome was P/F ratio, secondary outcomes were; static compliance, 28-day mortality, duration of MV and length of ICU-stay. Results: P/F ratio was 266 ± 44.5 in group I, 233 ± 53.9 in group II. Static compliance was 54.8 ± 6.6 in group I, 45.9 ± 3.8 in group II. IQR of duration of MV was 4-6 with a median value of 5 in group l, 6-11.7 with a median value of 7.5 in group ll. 28-day mortality was 6.7% in group l, 30% in group ll. The relative risk of mortality in group II is more or less 5 times in group I (RR 4.87 with 95%CI of 1.492-15.893). IQR of organ dysfunction-free days was 16-19 with a median value of 18 in group l, 0-12 with a median value of 10 in group ll. IQR of MV-free days was 22-24 with a median value of 23 in group l, 0-22 with a median value of 20 in group ll. Conclusion: LUS-guided PEEP showed improved oxygenation, compliance and decreased mortality, organ dysfunction, duration of MV and ICU compared with FiO 2-guided PEEP.