In 2009, a novel H1N1 influenza A virus emerged and spread worldwide, initiating a pandemic. Various isolates obtained from disparate parts of the world were shown to be uniformly resistant to the adamantanes but sensitive to the neuraminidase inhibitors oseltamivir and zanamivir. Over time, resistance to oseltamivir became more prevalent among pandemic H1N1 virus isolates, while most remained susceptible to zanamivir. The government has proposed the use of intravenous (i.v.) zanamivir to treat serious influenza virus infections among hospitalized patients. To use zanamivir effectively for patients with severe influenza, it is necessary to know the optimal dose and schedule of administration of zanamivir that will inhibit the replication of oseltamivir-sensitive and -resistant influenza viruses. Therefore, we performed studies using the in vitro hollow-fiber infection model system to predict optimal dosing regimens for zanamivir against an oseltamivir-sensitive and an oseltamivir-resistant virus. Our results demonstrated that zanamivir, at a dose of 600 mg given twice a day (Q12h), inhibited the replication of oseltamivir-sensitive and oseltamivir-resistant influenza viruses throughout the course of the experiment. Thus, our findings suggest that intravenous zanamivir, at a dose of 600 mg Q12h, could be used to treat hospitalized patients suffering from serious infections with oseltamivir-sensitive or -resistant influenza viruses.