The HIV envelope glycoprotein (Env) is composed of two non-covalently associated subunits: gp120 and gp41. Panning of phage-displayed antibody libraries against Env-based antigens has resulted mostly in selection of anti-gp120 antibodies. Native gp41 in the absence of gp120 is unstable. The use of gp41 fragments as antigens has resulted in selection of antibodies with relatively modest neutralizing activity. To enhance selection of antibodies specific for gp41 in the context of the whole Env we have developed a methodology termed competitive antigen panning (CAP). By using CAP we identified a novel gp41-specific human monoclonal antibody (hmAb), m48, from an immune library derived from long-term nonprogressors with high titers of broadly cross-reactive neutralizing antibodies (bcnAbs). M48 was only selected by CAP but not by the conventional preincubation methodology. It neutralized a panel of HIV-1 primary isolates from different clades in assays based on spreading infection in peripheral blood mononuclear cells (PBMCs) with potency higher than that of the well characterized broadly cross-reactive HIV-1-neutralizing antibodies IgG1 4E10 and Fab Z13. These results may have implications for selection of novel gp41-specific bcnAbs, and for the development of HIV-1 inhibitors and vaccine immunogens.