A comparison of inactivated whole influenza virus vaccine and purified influenza neuraminidase (NA) in BALB/c mice repeatedly challenged by homologous or heterologous H3N2 variant infections demonstrated an initial superiority of whole virus vaccine but the ultimate superiority of NA vaccine in immunization after one or two boosting infections. Parenteral administration of either vaccine followed by infection was much more effective than infection alone in the induction of either homologous or heterologous immunity. On the basis of this model simulation of human experience and other earlier studies, it seems that purified NA vaccine may offer an important new strategy as an initial step in immunization against influenza in humans.