Respiratory infections are generally caused by bacteria and viruses. In humans, viral respiratory disease is commonly associated with influenza A and B (IAV and IBV) viruses, as well as respiratory syncytial virus (RSV) and human metapneumovirus (hMPV). Epithelial cells of the respiratory tract are susceptible to infection by a range of respiratory viruses, resulting in virus replication and release. The ability of cells to induce host defense genes upon viral infection is a well-known antiviral mechanism, however the identity and/or the mechanism of action of the majority of such ‘restriction factors’ remains largely unknown. Identification and characterization of novel restriction factors for respiratory viruses is the first step towards development of therapeutics targeting restriction factors to limit and control viral infection of the airway epithelium. Recently, members of the membrane-associated RING-CH (MARCH) family proteins, namely MARCH2 and MARCH8, were reported to act as restriction factors against HIV-1, reducing the infectivity of virions released from infected cells by targeting the viral envelope glycoprotein. We generated stable cell lines with doxycycline-induced expression of 8 different human MARCH-family proteins to examine their ability to modulate respiratory virus infection. Although none of the MARCH proteins blocked the early stages of IAV infection (as measured by flow cytometry for newly-synthesized viral proteins), induced expression of MARCH8 was associated with reduced infectivity of IAV particles released from infected cells. Similarly, expression of MARCH8 reduced the infectivity of IBV and RSV, but not HMPV, released from infected cells. Mutations known to abrogate the E3 ligase activity of MARCH8 restored IAV infectivity, confirming that the ubiquitin ligase activity of MARCH8 is critical for its antiviral activity. Ongoing studies aim to define the composition of virions released from cells expressing MARCH8, as well as the particular viral proteins targeted by MARCH8.