Abstract Background A multimodal strategy to prevent nosocomial influenza was implemented in 2015–2016 in Grenoble Alpes University Hospital. Three modalities were implemented in all units: promotion of vaccination among healthcare workers, epidemiologic surveillance and communication campaigns. Units receiving a high number of patients with influenza implemented 2 additional modalities: improvement of diagnosis capacities and systematic surgical mask use. The main objective was to assess the effectiveness of the strategy for reducing the risk of nosocomial influenza. Methods A study was conducted retrospectively investigating 5 epidemic seasons (2014–2015 to 2018–2019) including all patients hospitalized with a positive influenza test at Grenoble Alpes University Hospital. The weekly number of nosocomial influenza cases was analyzed by Poisson regression and incidence rate ratios (IRR) were estimated. Results A total of 1540 patients, resulting in 1559 stays, were included. There was no significant difference between the 5 influenza epidemic seasons in the units implementing only 3 measures. In the units implementing the 5 measures, there was a reduction of nosocomial influenza over the seasons when the strategy was implemented compared to the 2014–2015 epidemic season (IRR = 0.56, 95% CI = 0.23–1.34 in 2015–2016; IRR = 0.39, 95% CI = 0.19–0.81 in 2016–2017; IRR = 0.50, 95% CI = 0.24–1.03 in 2017–2018; IRR = 0.48, 95% CI = 0.23–0.97 in 2018–2019). Conclusions Our data mainly suggested that the application of the strategy with 5 modalities, including systematic surgical mask use and rapid diagnosis, seemed to reduce by half the risk of nosocomial influenza. Further data, including medico-economic studies, are necessary to determine the opportunity of extending these measures at a larger scale.