The objective was to compare the effectiveness of repositioning every 2 or 4 h for preventing pressure ulcer development in patients in intensive care unit under mechanical ventilation (MV). This was a pragmatic, open-label randomized clinical trial in consecutive patients on an alternating pressure air mattress (APAM) requiring invasive MV for at least 24 h in a university hospital in Spain. Eligible participants were randomly assigned to groups for repositioning every 2 (n = 165) or 4 (n = 164) h. The primary outcome was the incidence of a pressure ulcer of at least grade II during ICU stay. A pressure ulcer of at least grade II developed in 10.3 % (17/165) of patients turned every 2 h versus 13.4 % (22/164) of those turned every 4 h (hazard ratio [HR] 0.89, 95 % confidence interval [CI] 0.46–1.71, P = 0.73). The composite end point of device-related adverse events was recorded in 47.9 versus 36.6 % (HR 1.50, CI 95 % 1.06–2.11, P = 0.02), unplanned extubation in 11.5 versus 6.7 % (HR 1.77, 95 % CI 0.84–3.75, P = 0. 13), and endotracheal tube obstruction in 36.4 versus 30.5 %, respectively (HR 1.44, 95 % CI 0.98–2.12, P = 0.065). The median (interquartile range) daily nursing workload for manual repositioning was 21 (14–27) versus 11 min/patient (8–15) (P < 0.001). A strategy aimed at increasing repositioning frequency (2 versus 4 h) in patients under MV and on an APAM did not reduce the incidence of pressure ulcers. However, it did increase device-related adverse events and daily nursing workload.