Tumor suppressor p53, the major cellular defense against tumor development, has recently been implicated in host antiviral defense. Previous studies have shown that p53 was induced at the apoptotic stage of influenza virus-infected cells. However. we found that p53 was induced not only at the apoptotic stage but also at the beginning phase of infection, showing a biphasic pattern with a first transient elevation apparent at the beginning phase of infection and a second elevation observable at the middle-late phase of infection. This up-regulation of p53 was independent of increased p53 transcription, but dependent on Virus adsorption and replication. The increased p53 was active and able to transactivate its downstream target genes, Such as interferon regulatory factor 9 (IRF9) and Bax. To our knowledge, this is the first report to describe a biphasic pattern of p53 accumulation in influenza virus-infected cells. (C) 2009 Elsevier Inc. All rights reserved.