The multivalent display of protein or peptide antigens on particles is thought to play an important role in promoting both in vitro B-cell activation and in vivo immunogenicity. However, the specific structural parameters that determine optimal recognition by B-cell receptors (BCRs) remain largely undefined. Through the use of peptide amphiphile scaffolds, we varied the nanoscale presentation of peptide epitopes on synthetic liposomes through changes in density, spacing, and molecular valency. Using transgenic B cells that express a BCR with defined affinities for specific peptides, we demonstrate that despite being intrinsically highly multivalent, liposomes displaying clustered dimeric and tetrameric peptide epitopes bind with higher avidity and induce greatly increased levels of activation and proliferation relative to a monomeric peptide controls. Furthermore, significantly increased antibody levels were observed following immunization in mice for dimeric and tetrameric peptides relative to monomeric peptides, suggesting that peptides optimized for BCR engagement improve humoral responses in vivo. These results demonstrate that the synthetic control of nanoscale epitope arrangements leads to substantial enhancement of B-cell activation, as well as improved immunogenicity.