CD4⁺ helper T cells are critical for protective immune responses and yet suboptimally primed in response to tumors. Cell-based vaccination strategies are under evaluation in clinical trials but limited by the need to derive antigen-presenting cells (APC) from patients or compatible healthy donors. To overcome these limitations, we developed CD4⁺ T cell–targeted synthetic microbead-based artificial APC (aAPC) and used them to activate CD4⁺ T lymphocytes specific for a tumor-associated model antigen (Ag) directly from the naive repertoire. In vitro, aAPC specifically primed Ag-specific CD4⁺ T cells that were activated to express high levels of CD44, produced mainly interleukin 2, and could differentiate into Th1-ike or Th2-like cells in combination with polarizing cytokines. I.v. administration of aAPC led to Ag-specific CD4⁺ T-cell activation and proliferation in secondary lymphoid organs, conferred partial protection against subcutaneous tumors, and prevented the establishment of lung metastasis. Taken together, our data support the use of cell-free, synthetic aAPC as a specific and versatile alternative to expand peptide-specific CD4⁺ T cells in adoptive and active immunotherapy. [Cancer Res 2008;68(8):3010–8]