The 2009 pandemic influenza A (H1N1) was a considerable public health concern worldwide. Significant morbidity and mortality were observed in complicated cases, despite the early administration of neuramidase inhibitors. The limitations of neuramidase inhibitor monotherapy have renewed interest in combination antiviral therapy or higher-dose oseltamivir therapy. Herein, we report our clinical experience and virological outcomes with high-dose oseltamivir or combination antiviral therapy in seriously complicated 2009 pandemic influenza A (H1N1) infection. Eight patients were treated with high-dose oseltamivir (150 mg twice a day), and 6 patients were treated with triple combination antiviral drugs (150 mg oseltamivir twice a day, 100 mg amantadine twice a day, and 300 mg ribavirin three times a day). Nine of 14 patients (64%) developed acute respiratory distress syndrome and 6 (43%) required mechanical ventilation. Viral clearance was obtained in 9 of 12 patients (75%) after 5 days of antiviral therapy. Two patients died within 5 days of antiviral therapy. The overall mortality rate was 29% (4/14).