Aim: Prone positioning improves oxygenation in patients with hypoxic respiratory failure. A pressure ulcer is a disturbing complication of prone positioning. The use of air mattresses and soft silicone dressing reduces the incidence of pressure ulcers in supine patients and prone intraoperative cases. We have compared the effect of two different strategies on the incidence of hospital-acquired pressure ulcers in patients undergoing prone ventilation for hypoxic respiratory failure. Materials and methods: We retrospectively analyzed the records of patients who underwent prone ventilation for hypoxic respiratory failure. Patients were divided into groups based on the hospital-acquired pressure ulcer prevention strategy used for prone patients. Patients in group S (Standard) were prone to the use of pillow support, headrest, and gel pads for pressure areas, while those in group O (Observation) were prone to air mattress along with soft silicone dressing and gel pads for pressure areas. The primary outcome was the incidence of pressure ulcers in both groups. The secondary outcomes were hemodynamic changes, oxygenation, and ventilatory parameters. Results: A total of 40 patients were included in the study, with equal distribution of 20 patients in each group. The incidence of hospital-acquired pressure ulcers was lower in group O as compared to group S (15 vs 25%, p = 0.35). No difference was seen in oxygenation, ventilation, or hemodynamic parameters. Conclusion: Use of air mattress and soft silicone dressing instead of pillow supports and headrest reduces the incidence of pressure ulcers in patients with prone ventilation (15 vs 25%, p = 0.35), which, in our opinion, is clinically significant. Albeit, there is no statistical difference in our study, we believe that a larger, well-designed, prospective study will show clinical and statistical difference. Reduced incidence of pressure ulcers will prevent facial scars, improves patient comfort, and will significantly contribute to better patient outcomes.