Oseltamivir is widely used as treatment for influenza virus A subtype H5N1 (hereafter, "H5N1") infection but, like any intervention, is not always effective.We used Avian Influenza Registry data from 10 countries to examine the risk of death in 215 patients with confirmed H5N1 infection who were treated with oseltamivir, according to viral clade, age, respiratory failure, and adjunctive treatment with corticosteroids or antibiotics.The median age of infected individuals was 18 years, and 50% were male. The highest fatality rate occurred in a country with clade 2.1 virus circulation, and the lowest occurred in countries with clade 2.2 virus circulation (P < .001). In univariate analyses, age of ≤5 years and treatment ≤2 days after symptom onset were protective against fatality. When accounting for all risk factors, early initiation of oseltamivir was found to be particularly effective in individuals without respiratory failure (odds ratio, 0.17; P = .04). Patients who had advanced respiratory failure requiring ventilatory support at the time of oseltamivir initiation were more likely to die from the episode of H5N1 infection than patients who did not (P < .001). Adjunctive therapy did not improve the likelihood of surviving the episode.Oseltamivir is especially effective for treating H5N1 infection when given early and before onset of respiratory failure. The effect of viral clade on fatality and treatment response deserves further investigation.