Human infections with avian influenza A (H5N1) are relatively rare but are associated with high mortality. As of July 5, 2010 there had been 500 cases and 296 fatalities. The influenza virus readily undergoes mutation and reassortment, and there are concerns that an H5N1 variant could be responsible for a future pandemic. The influenza neuraminidase inhibitors zanamivir and oseltamivir are approved for the treatment and prophylaxis of influenza. Oseltamivir is being used to treat H5N1 infections and the case has been made for a role for zanamivir; however, there are no case reports for the latter. Zanamivir is a potent inhibitor of H5N1, attains high lung concentrations immediately on administration, distributes into plasma at antiviral concentrations, has a low propensity for generating resistant virus, and retains activity against H275Y oseltamivir-resistant virus. There have been several reports of oseltamivir-resistant H5N1 arising during treatment with oseltamivir, and zanamivir retains effectiveness (in vitro or in vivo) against these isolates. Compassionate use of intravenous zanamivir for the treatment of seriously ill patients, including those with H275Y H1N1 infections, has also shown promising results. It is concluded that there is a role for zanamivir in treating H5N1 infections either as the approved, inhaled formulation in patients capable of using the Diskhaler, or as the intravenous formulation if compassionate use is warranted. The relatively small number of patients with these infections remains an obstacle to completion of clinical trials. Evidence is therefore likely to be based on carefully documented case reports, ideally in patients treated early in the course of the infection.