Immunostimulatory DNA sequences (ISS) are a potent Th1 adjuvant. We hypothesized that conjugation of ISS to protein antigens would strongly enhance their immunogenicity because both antigen and adjuvant (ISS) would be delivered to the same locale / antigen‐presenting cell. To test this hypothesis, we conjugated a 22‐mer immunostimulatory oligodeoxynucleotide (ISS‐ODN) to two test antigens of differing intrinsic immunogenicity, namely Escherichia coli β‐galactosidase and the HIV‐1 envelope glycoprotein gp120. We show that the antigen‐ISS conjugates rapidly induce Th1 cells secreting high levels of IFN‐γ, strong CTL activity, and high titer IgG2a and HIV‐neutralizing antibodies, exceeding gene and protein vaccination alone or immunization with mixtures of antigen and ISS‐ODN. The data suggest that this procedure generates a novel and unique vaccine that rapidly triggers strong humoral and cell‐mediated immunity.