BACKGROUND: Exposure to infected healthcare workers (HCWs) is a source of hospital-acquired (HA) influenza. We estimated the risk of HA influenza for hospitalized patients by rate of influenza vaccine coverage (IVC) of HCWs.METHODS: A case-case negative control study nested in a prospective cohort was conducted in 2 French university hospitals during 2 influenza seasons. Each inpatient with influenza-like illness (ILI) provided a nasal swab sample that was systematically analyzed for influenza virus by polymerase chain reaction (PCR) testing. An HA influenza case was a patient with a virological confirmation of influenza with onset of symptoms ?72 hours after admission to the ward. The IVC rate of HCWs in each participating ward was calculated from the data provided by the occupational health departments. A mixed-effect logistic regression was performed with adjustments on patient sex, age, the presence of a potential source of influenza on the ward in the 5 days prior to the start of the ILI, type of ward and influenza season.RESULTS: The overall HA influenza attack rate was 1.9 per 1,000 hospitalized patients. In total, 24 confirmed HA influenza cases and 141 controls were included. The crude odds ratio (OR) of HA influenza decreased from 0.52 (95% confidence interval [CI], 0.21-1.29) to 0.14 (95% CI, 0.03-0.63) when the IVC of HCWs increased from 20% to 40%. After adjustment, IVC ?40% was associated with a risk reduction of HA influenza (aOR, 0.07; 95% CI, 0.01-0.78).CONCLUSIONS: Considering a limited sample size, influenza vaccination of HCWs is highly suggestive of HA flu prevention among hospitalized patients.Trial Registration: clinicaltrials.gov identifier: NCT02198638.