Objectives To assess the impact of a hygiene-encouragement program on reducing infection rates (primary end point) by 5%. Design A cluster randomized study was carried out over a 5-month period. Settings and participants Fifty nursing homes (NHs) with 4345 beds in France were randomly assigned by stratified-block randomization to either a multicomponent intervention (25 NHs) or an assessment only (25 NHs). Intervention The multicomponent intervention was targeted to caregivers and consisted of implementing a bundle of infection prevention consensual measures. Interactive educational meetings using a slideshow were organized at the intervention NHs. The NHs were also provided with color posters emphasizing hand hygiene and a kit that included hygienic products such as alcoholic-based hand sanitizers. Knowledge surveys were performed periodically and served as reminders. Measurements The primary end point was the total infection rate (urinary, respiratory, and gastrointestinal infections) in those infection cases classified either as definite or probable. Analyses corresponded to the underlying design and were performed according to the intention-to-treat principle. This study was registered (#NCT01069497). Results Forty-seven NHs (4515 residents) were included and followed. The incidence rate of the first episode of infection was 2.11 per 1000 resident-days in the interventional group and 2.15 per 1000 resident-days in the control group; however, the difference between the groups did not reach statistical significance in either the unadjusted (Hazard Ratio [HR] = 1.00 [95% confidence interval (CI) 0.89–1.13]; P = .93]) or the adjusted (HR = 0.99 [95% CI 0.87–1.12]; P = .86]) analysis. Conclusion Disentangling the impact of this type of intervention involving behavioral change in routine practice in caregivers from the prevailing environmental and contextual determinants is often complicated and confusing to interpret the results.