Vaccination is the principle means of preventing seasonal and pandemic influenza and it's complications. A universal vaccine that induces broad immunity against multiple subtypes of influenza A viruses is a long-sought goal in medical research. Recently, we and others identified a family of human broadly neutralizing ''heterosubtypic'' antibodies (BnAbs) that bind to a highly conserved pocket on the stem of HA present in all Group 1 influenza viruses [1, 2] and block virus-host cell membrane fusion. These BnAbs were identified by recombinant H5 panning from antibody (Ab)-phage libraries that are constructed from nonimmune B cells [1] , immunoglobulin (Ig) M memory B cells of seasonal vaccinees [3] , or bone marrow of H5N1-infected ''bird-flu'' survivors [4] . BnAbs with similar properties have also been recovered from immortalized IgGexpressing memory B cells of seasonal vaccinees [5] . An unexpected finding from these studies is the frequent contribution of VH1-69 heavy chain genes to these BnAbs, suggesting that a large fraction (up to 10%) of the human naive B cell repertoire has the capability of responding to this conserved epitope [5, 6] . These observations raise additional questions as to whether such BnAbs are present in human serum and at ''protective'' levels, whether they exist as ''natural'' Abs, and/or whether are they generated during the immune response to influenza virus infection or vaccination [5, 7] . To explore these questions, we analyzed serum samples from H5N1 vaccinees and commercial intravenous immunoglobulin (IVIG) samples for their crossreactive binding and neutralization activity against different influenza A subtypes. We also utilized a representative BnAb, F10, for which the precise epitope was determined crystallographically [1] , to probe for heterosubtypic BnAbs directed against the highly conserved pocket on the HA stem.