Foreign DNA has been shown to impinge on immune cell function by an as yet unidentified mechanism. We and others have demonstrated that single‐stranded (ss) DNA containing the motif CpG flanked by two 5′ purines and two 3′ pyrimidines are mitogenic for B cells and activate macrophages to release tumor necrosis factor‐α, interferon‐γ, interleukin (IL)‐6 or IL‐12. Because of these proinflammatory responses we investigated if ssDNA would serve as a potential vaccine adjuvant. Here we show that CpG‐containing oligonucleotides represent a powerful adjuvant for both humoral and cellular immune responses. When ssDNA was incorporated into inocula, specific antibody titers of the IgG2 isotype were enhanced by greater than 100‐fold. Primary cytotoxic T lymphocyte responses generated to either unprocessed protein antigen or major histocompatibility complex class I‐restricted peptide were exceedingly strong. Evidence is also provided that oligomers directly influenced T cell receptor‐triggered T cell proliferation. Thus ssDNA oligomers may serve as inexpensive and safe vaccine adjuvants and, in addition, differential effects due to sequence may allow for directed responses.