Background. It is unclear if higher-dose oseltamivir provides benefit beyond standard dose in influenza patients who require hospitalization. Methods. A prospective, intervention study was performed in two acute general hospitals in Hong Kong over four seasonal peaks (2010-2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg bid oseltamivir for 5 days was site-allocated, which switched after two seasons. Subjects with pre-existing renal impairment (CrCl 40-60 ml/min) received 75 mg bid oseltamivir. Viral clearance by Day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured (HPLC-MS/MS). Results. Altogether, 41 and 114 patients received 150 mg and 75 mg bid oseltamivir respectively; their enrollment characteristics (mean±S.D. age: 61±18 vs. 66±16 yrs) and illness severity were comparable. Trough OC levels were higher in the 150 mg group (501.0±237.0 vs. 342.6±192.7 ng/ml). There were no significant differences in Day 5 viral RNA (44.7% vs. 40.2%) or culture (100.0% vs. 98.1%) negativity, RNA decline rate, and durations of fever, oxygen-supplementation and hospitalization. Results were similar when analyzed by study arms (all cases and among those without renal impairment). Sub-analysis of influenza B patients showed faster RNA decline rate (ANOVA, F-value 4.14; P=0.05) and clearance (Day 5, 80.0% vs. 57.1%) with higher-dose treatment. No oseltamivir-resistance was found. Treatments were generally well tolerated. Conclusions. We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B.