Frequent recent spillovers of subtype H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus into poultry and mammals, especially dairy cattle, including several human cases, increased concerns over a possible future pandemic. Here, we performed an analysis of epitope data curated in the Immune Epitope Database (IEDB). We found that the patterns of immunodominance of seasonal influenza viruses circulating in humans and H5N1 are similar. We further conclude that a significant fraction of the T-cell epitopes is conserved at a level associated with cross-reactivity between avian and seasonal sequences, and we further experimentally demonstrate extensive cross-reactivity in the most dominant T-cell epitopes curated in the IEDB. Based on these observations, and the overall similarity of the neuraminidase (NA) N1 subtype encoded in both HPAI and seasonal H1N1 influenza virus as well as cross-reactive group 1 HA stalk-reactive antibodies, we expect that a degree of pre-existing immunity is present in the general human population that could blunt the severity of human H5N1 infections.IMPORTANCEInfluenza A viruses (IAVs) cause pandemics that can result in millions of deaths. The highly pathogenic avian influenza (HPAI) virus of the H5N1 subtype is presently among the top viruses of pandemic concern, according to the WHO and the National Institute of Allergy and Infectious Diseases (NIAID). Previous exposure by infection and/or vaccination to a given IAV subtype or clade influences immune responses to a different subtype or clade. Analysis of human CD4 and CD8 T-cell epitope conservation between HPAI H5N1 and seasonal IAV sequences revealed levels of identity and conservation conducive to T cell cross-reactivity, suggesting that pre-existing T cell immune memory should, to a large extent, cross-recognize avian influenza viruses. This observation was experimentally verified by testing responses from human T cells to non-avian IAV and their HPAI H5N1 counterparts. Accordingly, should a more widespread HPAI H5N1 outbreak occur, we hypothesize that cross-reactive T-cell responses might be able to limit disease severity.