Here we evaluate the role of mast cells in infection with influenza A/H5N1 virus in immunized mice. CBA mice were immunized intramuscularly with formalin-inactivated A/Vietnam/1194/2004 (H5N1)NIBRG-14 (H5N1). Serum samples were obtained on days 7, 12, 14, 21 after immunization. At day 14, the mice were infected intranasally with the A/Indonesia/5/2005 (H5N1)IDCDC-RG2 (H5N1) influenza virus with half of the animals receiving a mixture of the antihistamines. 67% of the vaccinated mice were protected from the lethality compared to 43% in the PBS-immunized group. Administration of antihistamines increased survival up to 85%–95%. Immunohistochemical examination using CD117 staining of the lungs demonstrated a larger quantity of activated mast cells after infection of immunized mice compared to mock-immunized mice. This was correlated to increased histamine level in the lungs and blood. Our experimental results suggest the involvement of mast cells and the histamine they produce in the pathogenesis of influenza infection in case of incomplete formation of the immune response to vaccination and mismatch of the vaccine and infection influenza viruses.