Prophylaxis is sometimes offered to inpatients who share a room with, or individuals who have been in close contact with, patients who have contracted influenza. In our hospital, 5-day prophylactic oseltamivir has been used as a standard procedure. Here, we investigated the effectiveness of this post-exposure prophylaxis for inpatients and healthcare professionals, as well as its effect on hospital management. The study period was 5 years from fiscal year 2013 to fiscal year 2017, and the effectiveness outcome was the secondary infection rate. Medication costs for this prophylaxis were compared with those for oseltamivir used according to the package insert. The secondary infection rates were 3.0% and 0.5% in 133 inpatients and 434 healthcare professionals who had received post-exposure oseltamivir, respectively. The medication costs were reduced by 50% compared with the estimated costs for 10-day oseltamivir administration. The effectiveness of 5-day prophylactic oseltamivir was similar to or higher than that reported previously, indicating that this prophylaxis was effective. Moreover, 5-day post-exposure prophylactic oseltamivir is expected to reduce the prolongation of hospital stay and influenza outbreaks and thus contribute to hospital management.