Background. Epidemiologic, clinical, and laboratory data suggest that H5N1 influenza viruses are transmitted through and predominantly affect the respiratory system of mammals. Some data suggest digestive system involvement. However, direct evidence of alimentary transmission and infection in mammals is lacking. Methods. Infection with and pathogenesis of 4 H5N1 viruses were assessed in mice and ferrets inoculated intranasally or intragastrically with virus in liquid. In addition, ferrets were fed infected raw chicken meat or minced meat administered into the stomach by gavage with a tube. Results. Only one virus, A/Whooper swan/Mongolia/244/05, was able to infect mice after intragastric inoculation in liquid, whereas no evidence of infection was observed in ferrets after intragastric inoculation. Consumption of infected meat by ferrets resulted in respiratory system infection only (due to A/Muscovy duck/Vietnam/209/05 and A/Whooper swan/Mongolia/244/05 viruses) or in both severe respiratory and systemic infection with predominant involvement of the liver, pancreas, and large and small intestine (due to A/Vietnam/1203/04 virus). Direct intragastric exposure to infected meat (A/Vietnam/1203/04 virus) resulted in lethal systemic disease mainly affecting the intestine, liver, and pancreas but not involving the lungs. Conclusions. Our results demonstrated that exposure of the digestive system to H5N1 influenza viruses could initiate infection either through the tonsil, with spread to respiratory tissues, or through intestinal infection, with spread to the liver and pancreas.