The identification of T cell epitopes is crucial for the understanding of the host immune response during infection. While much is known about the MHC class I-restricted response following influenza virus infection of C57BL/6 mice, with over 16 CD8 epitopes identified to date, less is known about the MHC class II-restricted response. Currently, only a few I-Ab-restricted T helper epitopes have been identified. Therefore, several important questions remain about how many class II epitopes exist in this system and whether these epitopes are evenly distributed within the most abundant viral proteins. In order to address these questions, we analyzed the repertoire of epitopes that drive the CD4+ T cell response to influenza virus infection in C57BL/6 (H-2b) mice. Using a panel of overlapping peptides from each of the viral proteins we show that approximately 20-30 epitopes drive the CD4 T cell response and that the majority of these peptides are derived from the NP and HA proteins. We were also able to demonstrate that vaccination with one of the newly identified epitopes, HA211-225/Ab, resulted in increased epitope-specific T cell numbers and a significant reduction in viral titers following influenza virus challenge. © 2005 Elsevier Ltd. All rights reserved.