The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8as amodel, linear andpolycyclic synthetic aromatic compounds are introducedat selected sites. Molecular dynamics simulations predict the favorable interactions of these synthetic compounds with the viral lipidmembrane, where the epitope of the HIV-1 glycoprotein Env is located. Chemicalmodification of 10E8 with aromatic acetamides facilitates the productive and specific recognition of the native antigen, partially buriedin the crowdedenvironmentof the viralmembrane, resultingin adramatic increase of its capacity to block viral infection. These observations support the harnessing of interfacial affinity through site-selective chemical modification to optimize the function of antibodies that target membrane-proximal epitopes.