Subunit and intact influenza A virus vaccines have been compared with infectious virus in a mouse model for their ability to induce memory for cross-reactive cytotoxic T cell responses and to protect mice from challenge with different subtypes of influenza A virus. There is an overall correlation between secondary cytotoxic T cell responses and cross-protection. The most long-lasting and successful cross-protection was observed after intranasal infection with influenza virus A/X31 (H3 N2) that replicates efficiently in mice and induces high levels of memory for cross-reactive cytotoxic T cell responses. Short-lasting cross-protection and low levels of T cell-mediated cytotoxicity were associated with infection by A/USSR (H1 N1) virus, that replicates to lower titers in mice, or after multiple injections of inactivated whole virus vaccine. No cross-protection to challenge with heterologous influenza virus was detectable after 1-2 injections of HANA influenza subunit vaccine which failed to prime hosts for cytotoxic T cell responses. These findings may have important implications for vaccination strategy. If cytotoxic T cells play a role in the protection of humans from influenza, live attenuated vaccines should be considered instead of the currently recommended inactivated virus or subunit vaccines.