Current evidence suggests that immunotherapy for cancer or infectious diseases will require the activation of CD4(+) T cells in addition to the activation of cytotoxic CD8(+) T cells. To complement and overcome some of the limitations of dendritic-cell-based vaccines and ex vivo expansion of human T cells, we sought to engineer artificial antigen-presenting cells (aAPCs) for the stimulation of antigen-specific human CD4(+) T cells. We have designed a variety of aAPCs using magnetic beads as a scaffold on which to coat HLA-peptide tetrameric complexes along with costimulatory molecules such as anti-CD28. Here, we tested various forms of conjugation of the tetramers onto beads, characterized the relative concentration of antigen available on the surface of the beads, and evaluated the ability of different types of beads to promote activation of antigen-specific CD4(+) T cells. We find that an indirect coating of HLA-peptide tetramers on beads via an anti-Class II antibody provides specific stimulation of antigen-specific CD4(+) T cells.