OBJECTIVE: To investigate the clinical effectiveness of three nursing-home-wide repositioning intervals (2-, 3-, or 4-hour) without compromising pressure injury (PrI) incidence in 4 weeks. METHODS: An embedded pragmatic cluster randomized controlled trial was conducted in nine nursing homes (NHs) that were randomly assigned to one of three repositioning intervals. Baseline (12 months) and 4-week intervention data were provided during the TEAM-UP (Turn Everyone And Move for Ulcer Prevention) study. Intervention residents were without current PrIs, had PrI risk (Braden Scale score) ≥10 (not severe risk), and used viable 7-inch high-density foam mattresses. Each arm includes three NHs with an assigned single repositioning interval (2-, 3-, or 4-hour) as standard care during the intervention. A wireless patient monitoring system, using wearable single-use patient sensors, cued nursing staff by displaying resident repositioning needs on conveniently placed monitors. The primary outcome was PrI incidence; the secondary outcome was staff repositioning compliance fidelity. RESULTS: From May 2017 to October 2019, 1,100 residents from nine NHs were fitted with sensors; 108 of these were ineligible for some analyses because of missing baseline data. The effective sample size included 992 residents (mean age, 78 ± 13 years; 63% women). The PrI incidence during the intervention was 0.0% compared with 5.24% at baseline, even though intervention resident clinical risk scores were significantly higher (P < .001). Repositioning compliance for the 4-hour repositioning interval (95%) was significantly better than for the 2-hour (80%) or 3-hour (90%) intervals (P < .001). CONCLUSIONS: Findings suggest that current 2-hour protocols can be relaxed for many NH residents without compromising PrI prevention. A causal link was not established between repositioning interval treatments and PrI outcome; however, no new PrIs developed. Compliance improved as repositioning interval lengthened.