Antibody-dependent cellular cytotoxicity (ADCC) correlated with a reduced risk of infection from HIV-1 in the RV144 vaccine trial, the only HIV-1 vaccine trial to date to show any efficacy. Antibodies specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (cluster A region) were induced in the RV144 trial and their ADCC activities were implicated in the vaccine efficacy. We present structural analyses of the antigen epitope targets of several RV144 antibodies specific for this region and C11, an antibody induced in natural infection, to show what the differences are in epitope specificities, mechanism of antigen recognition, and ADCC activities of antibodies induced by vaccination and during the course of HIV infection. Our data suggest that the truncated AIDSVAX gp120 variants used in the boost of the RV144 regimen may have shaped the vaccine response to this region, which could also have contributed to vaccine efficacy.