In this study, we describe a human monoclonal antibody named PN-SIA49 recognizing a highly conserved epitope on the stem region of HA and featuring one of the strongest in-vitro neutralizing activity described so far against a broad spectrum of viruses belonging to different influenza subtypes (H1, H2 and H5). Furthermore, we describe its protective activity in mice after lethal challenges with H1N1 and H5N1 viruses suggesting its potential as a broad-spectrum monoclonal antibody for treatment of influenza virus infection.