The study investigates the antibody CR6261, which recognizes a highly conserved epitope in the membrane-proximal stem of the hemagglutinin (HA) protein of influenza viruses. CR6261 neutralizes the virus by blocking conformational rearrangements associated with membrane fusion, providing immunity to diverse influenza subtypes and protection against future pandemic viruses. The crystal structures of CR6261 Fab in complex with HA from the 1918 H1N1 pandemic virus and a recent H5N1 avian influenza virus were determined at 2.2 and 2.7 Å resolutions. CR6261 binds to a region in the HA2 A-helix, primarily using its heavy chain, and interacts with residues in the HA1 stem. The epitope is highly conserved across all 16 influenza A subtypes, suggesting its critical role in membrane fusion. This finding provides a new lead for the design of improved vaccines and antibody-based therapies for influenza.The study investigates the antibody CR6261, which recognizes a highly conserved epitope in the membrane-proximal stem of the hemagglutinin (HA) protein of influenza viruses. CR6261 neutralizes the virus by blocking conformational rearrangements associated with membrane fusion, providing immunity to diverse influenza subtypes and protection against future pandemic viruses. The crystal structures of CR6261 Fab in complex with HA from the 1918 H1N1 pandemic virus and a recent H5N1 avian influenza virus were determined at 2.2 and 2.7 Å resolutions. CR6261 binds to a region in the HA2 A-helix, primarily using its heavy chain, and interacts with residues in the HA1 stem. The epitope is highly conserved across all 16 influenza A subtypes, suggesting its critical role in membrane fusion. This finding provides a new lead for the design of improved vaccines and antibody-based therapies for influenza.