In total, we tested the activity and synergy of the TCAD regimen against six amantadine-resistant viruses, including three strains of 2009 H1N1, and two oseltamivir-resistant viruses. The viruses tested in this study come from the three subtypes that cause significant morbidity and mortality in humans (H1N1, H3N2, and H5N1), and include seasonal, avian, and pandemic strains. The double combinations of amantadine/oseltamivir carboxylate, amantadine/ribavirin, and ribavirin/oseltamivir carboxylate were additive against 2009 H1N1, and ranged from additive to moderately synergistic against the other viruses (data not shown). In contrast, with the exception of the duck H5N1 virus, we found that the TCAD regimen was synergistic at clinically achievable concentrations of all three drugs, and that the synergy of the TCAD regimen was greater than that of any double antiviral drug combination. These data suggest that the TCAD regimen may have broad-spectrum antiviral activity against circulating influenza A viruses, including strains that are resistant to either classes of antivirals. To date, most influenza A strains in circulation (,99%) are resistant to either the adamantanes or oseltamivir, and not to both [31] , and thus are expected to be susceptible to the TCAD regimen. Currently, rapid diagnostic tests are not available to determine the susceptibility profile of influenza viruses in real time, and thus clinicians do not often have the necessary information with which to guide appropriate antiviral use. The availability of a broad-spectrum antiviral therapy that would be effective against the majority of circulating strains regardless of the susceptibility would be of high clinical utility.