The anti-influenza effects of camostat, a serine protease inhibitor, on in vivo influenza infections were evaluated. Mice which received non-adapted human influenza viruses intranasally, developed a reproducible infection with very low mortality. The infection was readily detected by the recovery of the virus from an oropharyngeal swab. Five-week-old ICR mice received intraperitoneal injections of saline (control), amantadine (known positive drug), or camostat, after infection with influenza A/Taiwan/1/86 virus. Virus detection was performed on day 1, 2, 3, 5, and 7 of postinfection. Both camostat and amantadine were effective in ameliorating mouse influenza. On day 5, mice injected with camostat (45%) or amantadine (50%) showed a lower virus secreting rate than those receiving saline (90%). Additionally, camostat showed strong anti-influenza effects on an amantadine-resistant type A virus and a type B virus infection in vitro. The results show that blocking the hemagglutinin cleavage is an effective target for development of an anti-influenza agent. They also demonstrate that virus detection from the oropharynx of mice, infected with non-adapted virus, is a useful in vivo influenza model.