Immunization with live influenza virus expands Th1 memory cells and facilitates more rapid recovery after heterosubtypic virus challenge. Immunization with inactivated virus generates a Th2 response and does not lead to heterosubtypic immunity. Creation of a Th1 priming environment by the inclusion of interleukin (IL)-12 with antibodies to IL-4 converted the response against inactivated virus to a Th1 response that was able to facilitate virus clearance upon heterosubtypic virus challenge. Evaluation of memory responses of mice immunized by the various protocols demonstrated that the type of immunization imprints T cell memory, dictating the nature of the response to subsequent infection. After live virus challenge, expansion of Th1 cells seems to facilitate the generation of cytotoxic T lymphocytes from naïve precursors. This latter finding may be the mechanism by which inactivated virus immunization in a Th1 cytokine context mediates heterosubtypic immunity.