Context/Objective: Medically serious pressure injuries (MSPrIs), a common complication of spinal cord injury (SCI), have devastating consequences on health and well-being and are extremely expensive to treat. We aimed to test the efficacy of a lifestyle-based intervention designed to reduce incidence of MSPrIs in adults with SCI. Design: A randomized controlled trial (RCT), and a separate study wing involving a nonrandomized standard care control group. Setting: Rancho Los Amigos National Rehabilitation Center, a large facility serving ethnically diverse, low income residents of Los Angeles County. Participants: Adults with SCI, with history of one or more MSPrIs over the past 5 years: N=166 for RCT component, N=66 in nonrandomized control group. Interventions: The Pressure Ulcer Prevention Program, a 12-month lifestyle-based treatment administered by healthcare professionals, largely via in-home visits and phone contacts. Outcome Measures: Blinded assessments of annualized MSPrI incidence rates at 12 and 24 months, based on: skin checks, quarterly phone interviews with participants, and review of medical charts and billing records. Secondary outcomes included number of surgeries and various quality-of-life measures. Results: Annualized MSPrI rates did not differ significantly between study groups. At 12 months, rates were .56 for intervention recipients, .48 for randomized controls, and .65 for nonrandomized controls. At follow-up, rates were .44 and .39 respectively for randomized intervention and control participants. Conclusions: Evidence for intervention efficacy was inconclusive. The intractable nature of MSPrI threat in high-risk SCI populations, and lack of statistical power, may have contributed to this inability to detect an effect. Trial Registration: ClinicalTrials.gov NCT01999816