Most retroviruses induce severe immunosuppression during acute infection. We have used the Friend retrovirus mouse model to demonstrate that immunostimulatory B-type CpG oligodeoxynucleotides (ODN) have a protective effect against retrovirus-induced suppression of antibody responses to potent B-cell antigens. CD8+ T cells were critical for effective treatment with CpG-ODN, since in vivo depletion of these cells from treated mice impaired protection from retrovirus-induced immunosuppression. Protection also required IFN-gamma, as neutralization of this cytokine abolished the therapeutic effect of CpG-ODN. These findings may have implications for the treatment of immunosuppressive virus infections.