BACKGROUND:A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in pre-clinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza. METHODS:Data from two separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes includes rate of clinical improvement, defined as a decrease of 2 categories on a 7-category ordinal scale, and viral RNA detectability over time. Sub-hazard ratio (sHR) was estimated by Fine and Gray model for competing risks. RESULTS:In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on Day 14 occurred in the combination group was higher than in monotherapy group (62.5% vs 42.2%, p=0.0247). The adjusted sHR for combination therapy was 2.06 (95%CI: 1.3-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than oseltamivir group (67.5% vs 21.9%, p<0.01). No significant differences were observed in mortality or other outcomes. CONCLUSIONS:Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial.