Infection with human influenza A virus can reach cataclysmic levels, with 40 or more million deaths arising from the 1918 pandemic. Preventative and therapeutic measures have improved since that time, but new approaches are needed. Here, we describe one such new approach--the interfering vaccine, which has two activities--it prophylactically prevents influenza, and at the same time converts an otherwise lethal infection into one that is avirulent and immunizing. Mice treated in this way develop a solid immunity that protects them against a subsequent challenge with homologous virus, and to a lesser extent from challenge with heterologous influenza A viruses. The interfering vaccine comprises non-infectious, defective interfering (DI) influenza A virus. Prophylaxis is mediated directly by DI RNA, and results from interference with the replication of the infecting virus. However, interference is incomplete, and there is sufficient wild-type virus multiplication to stimulate a virus-specific natural immunity. As the replication mechanism is common to all influenza A viruses, an interfering vaccine should protect from, and permit immunity to be developed to all influenza A viruses. Indeed, we demonstrate protection against two viruses with antigenically unrelated HA and NA proteins. Thus an interfering vaccine, unlike the conventional vaccine, is independent of the antigenicity of the infecting virus. In principle, interfering vaccines derived from other virus systems could also be developed.