IFITM3 is critical for limiting the severity of influenza virus infections in humans and mice. Optimal antiviral activity of IFITM3 is achieved when it is present at high levels within cells. Our results indicate that the E3 ubiquitin ligase NEDD4 decreases baseline IFITM3 levels by ubiquitinating IFITM3 and promoting its turnover. Depleting NEDD4 from cells results in IFITM3 accumulation and greater resistance to infection by influenza viruses.