Bacterial DNA contains immunostimulatory motifs that trigger an innate immune response characterized by the production of predominantly Th1-type cytokines. These motifs consist of an unmethylated CpG dinucleotide flanked by two 5′ purines and two 3′ pyrimidines. We examined whether synthetic oligodeoxynucleotides (oligos) expressing these motifs would act as adjuvants to boost the immune response to DNA- and protein-based immunogens. In vivo experiments demonstrate that CpG-containing oligos augment antigen-specific serum antibody levels by up to tenfold, and IFNγ production by up to sixfold. These effects were optimized by physically linking the CpG-containing motifs to the immunogen.