Abstract Background and objectives: The objective of this study was to investigate the use of early APRV mode as a lung protective strategy compared to conventional methods with regard to ARDS development. Methods: The study was designed as a randomized, non-blinded, single-center, superiority trial with two parallel groups and a primary endpoint of ARDS development. Patients under invasive mechanical ventilation who were not diagnosed with ARDS and had Lung Injury Prediction Score greater than 7 were included in the study. The patients were assigned to APRV and P-SIMV + PS mode groups. Results: Patients were treated with P-SIMV+PS or APRV mode; 33 (50.8%) and 32 (49.2%), respectively. The P/F ratio values were higher in the APRV group on day 3 (p = 0.032). The fraction of inspired oxygen value was lower in the APRV group at day 7 (p = 0.011).While 5 of the 33 patients (15.2%) in the P-SIMV+PS group developed ARDS, one out of the 32 patients (3.1%) in the APRV group developed ARDS during follow-up (p = 0.197). The groups didn’t differ in terms of vasopressor/inotrope requirement, successful extubation rates, and/or mortality rates (p = 1.000, p = 0.911, p = 0.705, respectively). Duration of intensive care unit stay was 8 (2-11) days in the APRV group and 13 (8-81) days in the P-SIMV+PS group (p = 0.019). Conclusions: The APRV mode can be used safely in selected groups of surgical and medical patients while preserving spontaneous respiration to a make benefit of its lung-protective effects. In comparison to the conventional mode, it is associated with improved oxygenation, higher mean airway pressures, and shorter intensive care unit stay. However, it does not reduce the sedation requirement, ARDS development, or mortality.