Background: Globally circulating strains of HIV-1 exhibit an extraordinary degree of genetic variation, which constitutes a major obstacle to AIDS vaccine development. To test whether immunogen based on a consensus sequence could minimize this diversity, we generated a “universal” env gene (gp160) from the consensus sequences of all major HIV-1 group M subtypes. The deduced protein sequence of this “consensus of the consensus” env gene differed from contemporary group M Env protein sequences by 12%, while the latter differed from each other by 24%, on average. The consensus env gene (gp120) was transfected into 293T-cells and expressed Env proteins from the cell culture supernatant were analyzed for antigenic structure and biological function. BiaCore analyses showed that the group M consensus gp120 bound to sCD4 as well as broadly neutralizing (2G12, b12) and non-neutralizing antibodies (A32, T8). Moreover, MAb 17b binding to the consensus and conventional gp120s was increased to similar extents upon sCD4 or A32 addition, so both gp120s undergo appropriate conformational changes. Western blot analysis showed that the consensus gp120 reacted equally well with subtype B and C patient sera, while subtype B (JRFL) and C (96ZM651) glycoproteins reacted best with sera from their respective subtypes. ELISA assays confirmed the presence of cross-reactive epitopes among subtype B and C envelopes. The consensus Env gp120 and gp140 have been expressed in recombinant vaccinia viruses for immunogenicity studies. Overall, the group M consensus and the contemporary Env glycoproteins share structural and functional similarities, but the consensus glycoprotein is recognized by a more diverse range of binding antibodies from infected people. These promising results suggest that consensus Env glycoproteins warrant evaluation as a “universal” immunogen.