In this study, we sought to evaluate the activity and synergy of the TCAD regimen against influenza viruses which were resistant to amantadine or oseltamivir. Our data showed that against amantadine-resistant viruses -both seasonal and 2009 H1N1and oseltamivir-resistant seasonal viruses, the TCAD regimen was strongly synergistic, and the synergy of the TCAD regimen was greater than the synergy of any double combination. Surprisingly, we found that amantadine and oseltamivir contributed to the synergy of the TCAD regimen at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our findings highlight the utility of the TCAD regimen as a potential approach to address the current limitations of antiviral potency and drug resistance, and as a viable broad-spectrum therapeutic option for serious influenza virus infection.