This large publicly funded clinical trial examined the effect of combination neuraminidase inhibitor antiviral therapy in influenza, as compared to each monotherapy plus placebo. It showed that, during the prepandemic winter of 2009 with a predominance of H3N2 viruses (more than 85%) in France, the oseltamivir-zanamivir combination seemed less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy in adults with seasonal influenza A virus infection.