This randomized phase 1b study evaluated the pharmacokinetics/pharmacodynamics of conventional-dose (30-75 mg twice daily [BID]) vs triple-dose (90-225 mg BID; weight-adjusted) oseltamivir for treatment of influenza in severely immunocompromised children <13 years. Oseltamivir carboxylate (OC) Cmax and AUC0-12h were ~2-fold higher with triple-dose vs conventional-dose oseltamivir. Increased dose/exposure of oseltamivir/OC did not improve virological outcomes or reduce viral resistance. Median time to cessation of viral shedding was similar with triple-dose and conventional-dose oseltamivir (150.7 vs 157.1 hours, respectively); median time to alleviation of baseline fever was longer with conventional-dose oseltamivir (28.4 vs 11.3 hours). No new safety signals were identified.