Selecting the B strain for inclusion in a trivalent seasonal influenza vaccine has been difficult because two distinct influenza B lineages frequently co-circulate, prompting consideration of a quadrivalent vaccine containing two A and two B strains. Because interference among wild-type influenza viruses is a well-documented phenomenon and viral replication is required to elicit protection by the licensed live-attenuated influenza vaccine (LAIV; MedImmune, LLC, Gaithersburg, MD, USA), a potential quadrivalent formulation raises considerations of interference among the LAIV strains contained in the vaccine. We reviewed the available clinical and nonclinical literature to understand the potential impact of viral interference on immunogenicity, efficacy and shedding of LAIV strains. We have found no clinically significant evidence of viral or immune interference affecting efficacy of LAIV strains in multivalent vaccine formulations. Future clinical studies should compare the safety and immune responses of children and adults to licensed trivalent and investigational quadrivalent LAIV formulations.