Our data suggests that a triple combination antiviral drug (TCAD) composed of amantadine, ribavirin, and oseltamivir may be an effective and viable therapeutic option for the treatment of pandemic and seasonal influenza infection. The body of data presented in this report validates the TCAD hypothesis, which states that for any given susceptible or resistant circulating influenza virus, at least two, and in some cases all three, drugs in TCAD will be active. Furthermore, the TCAD regimen appears to overcome baseline drug resistance and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza. The safety, pharmacokinetics, distribution, and metabolism of amantadine, ribavirin, and oseltamivir as single agents are well understood, and it is not expected that co-administration of the three drugs will result in substantially increased risk to patients compared to the administration of the individual drugs. In addition, all three double combinations have been tested in humans without adverse effects, including amantadine plus oseltamivir [39] , amantadine plus ribavirin [40] , and ribavirin plus oseltamivir [41] . Clinical trials to assess the efficacy and safety of TCAD for the treatment of influenza have been initiated, and will provide important data on the use of TCAD against both pandemic and seasonal influenza.