It has been proposed that HIV-1-neutralizing 2F5 and 4E10 monoclonal antibodies recognize gp41 ectodomain pretransmembrane sequences in the context of the membrane interface. With the aim of evaluating lipid-bilayer surface effects on recognition, we use phospholipid model systems to investigate the ability of 2F5 and 4E10 to transfer into membrane interfaces and bind epitope sequences immersed therein. The experimental data support the predicted tendencies for partitioning and recognition of membrane-bound epitopes, albeit with lower affinity in the case of 2F5. Our findings support the existence of two different recognition mechanisms at membrane surfaces: the association of 2F5 with the interface possibly prevents epitope immersion into the bilayer, and 4E10 membrane association might allow recognition of the membrane-bound epitope. We discuss the relevance of these observations for the design of immunogens aimed at eliciting 2F5- and 4E10- like humoral responses.