The clinical course of pandemic H1N1 2009 influenza can be severe, particularly in the very young and patients with comorbidities. Pandemic H1N1 2009 is sensitive to the antiviral agents oseltamivir and zanamivir but is resistant to the M2 inhibitors. Although few clinical data are yet available, treatment of pandemic H1N1 2009 influenza in hospital settings with oseltamivir or zanamivir appears to be beneficial. In hospitalized patients with severe influenza treated with oseltamivir, mortality and length of stay are significantly reduced, and viral load is reduced more quickly than in untreated patients. In patients at high risk treated with oseltamivir or zanamivir, reductions in the risk of complications and mortality after treatment have been demonstrated with oseltamivir and zanamivir, although there are fewer data on the latter. There is no evidence yet that other antiviral agents are effective in severe or pandemic H1N1 2009 influenza. Current World Health Organization guidance strongly recommends the use of oseltamivir for severe or progressive infection with pandemic H1N1 2009, with zanamivir as an alternative if the infecting virus is oseltamivir-resistant. Very little resistance to oseltamivir has been found to date.