Highly pathogenic avian influenza (HPAI) H5N1 virus infections have caused unprecedented morbidity and mortality in different species of domestic and wild birds in Asia, Europe, and Africa. In our previous study, we demonstrated the susceptibility and potential epidemiologic importance of H5N1 HPAI virus infections in Canada geese. In this study, we investigated the potential of preexposure with North American lineage H3N8, H4N6, and H5N2 low pathogenicity avian influenza (LPAI) viruses to cross-protect Canada geese against a lethal H5N1 HPAI virus challenge. Based on our results, birds that were primed and boosted with an H5N2 LPAI virus survived a lethal H5N1 challenge. In contrast, only two of five birds from the H3N8 group and none of the birds preexposed to H4N6 survived a lethal H5N1 challenge. In vitro cell proliferation assays demonstrated that peripheral blood mononuclear cells collected from each group were no better stimulated by homologous vs. heterologous antigens.