Given that virtually all seasonal H3N2 and 2009 H1N1 strains are resistant to amantadine, and virtually all currently circulating seasonal H1N1 strains are resistant to oseltamivir, the pharmacologic rationale for the development of a triple combination antiviral drug (TCAD) composed of amantadine, ribavirin, oseltamivir is that at least two, and possibly three drugs, in the TCAD regimen will be active against all of these viruses. A number of studies have evaluated double combinations of antivirals [21] [22] [23] [24] [25] [26] [27] against influenza A infection in vitro, and Hayden et al. have tested a triple combination of two antivirals with human interferon a [28] . However, there have been few reports on the effects of drug combinations on resistant influenza viruses [26, 27, 29] . Recently, Smee et al. evaluated the effects of double combinations of amantadine, ribavirin, and oseltamivir against the same amantadine-resistant H5N1 virus used in this study (A/Duck/MN/1525/81) [26] . The authors found that the presence of amantadine in double combinations did not provide added benefit over the second drug alone, either in cell culture or in mouse models.