Background.  Current oseltamivir prophylactic regimens may not be as effective against highly pathogenic H5N1 influenza viruses as they are against less pathogenic strains. An optimal regimen is urgently needed. Methods.  Ferrets were given the neuraminidase inhibitor oseltamivir orally for 10 days (5 or 10 mg/kg once daily or 2.5 or 5 mg/kg twice daily). Prophylaxis was initiated 1 day before infection, and oseltamivir was given 4 h before the ferrets were inoculated with a lethal dose of A/Vietnam/1203/04 (H5N1) influenza virus. Results. At a dose of 5 mg/kg once daily, oseltamivir prevented death but not clinical signs of infection in ferrets; severe pathology was observed in the lungs, brain, and liver. At 10 mg/kg once daily, oseltamivir reduced clinical symptoms and systemic virus replication, but pathology was observed in the internal organs. The best results were obtained at a dose of 2.5 or 5 mg/kg given twice daily. Both regimens resulted in 100% survival and the absence of clinical symptoms, systemic virus spread, and organ pathology. Serum antibody titers were comparable across regimens and were sufficient to protect against rechallenge. Conclusions. @nbsp; An increased dose of oseltamivir or twice-daily administration effectively protects ferrets against morbidity and mortality caused by H5N1 infection and does not interfere with the development of protective antibodies against subsequent H5N1 infection.