Objective: To conduct an intervention trial of a "best practices" musculoskeletal injury prevention program designed to safely lift physically dependent nursing home residents. Design: A pre-post intervention trial and cost benefit analysis at six nursing homes from January 1995 through December 2000. The intervention was established in January 1998 and injury rates, injury related costs and benefits, and severity are compared for 36 months pre-intervention and 36 months post-intervention. Participants: A dynamic cohort of all nursing staff (n = 1728) in six nursing homes during a six year study period. Intervention: "Best practices" musculoskeletal injury prevention program consisting of mechanical lifts and repositioning aids, a zero lift policy, and employee training on lift usage. Main outcome measures: Injury incidence rates, workers' compensation costs, lost work day injury rates, restricted work day rates, and resident assaults on caregivers, annually from January 1995 through December 2000. Results: There was a significant reduction in resident handling injury incidence, workers' compensation costs, and lost workday injuries after the intervention. Adjusted rate ratios were 0.39 (95% confidence interval (CI) 0.29 to 0.55) for workers' compensation claims, 0.54 (95% CI 0.40 to 0.73) for Occupational Safety and Health Administration (OSHA) 200 logs, and 0.65 (95% CI 0.50 to 0.86) for first reports of employee injury. The initial investment of $158 556 for lifting equipment and worker training was recovered in less than three years based on post-intervention savings of $55 000 annually in workers' compensation costs. The rate of post-intervention assaults on caregivers during resident transfers was down 72%, 50%, and 30% based on workers' compensation, OSHA, and first reports of injury data, respectively. Conclusions: The "best practices" prevention program significantly reduced injuries for full time and part time nurses in all age groups, all lengths of experience in all study sites.