We have previously presented indirect evidence that both specific immunosuppression and lymphocyte mitogenicity induced in mice by p36, a proteinaceous factor of virulence produced by porcine monocytes infected by African swine fever virus, were consistent with a Th2-driven response. Here we show: (1) Interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNA expression in the spleen and thymus of C57BL/6 mice were displayed early after p36 inoculation. The expression of thymic IL-10 mRNA occurred, however, later than that of IL-4 mRNA. (2) Increased serum levels of these two cytokines were also soon detected after the protein inoculation. (3) Both immunosuppressive and mitogenic effects of p36 were absent in IL-4 gene-targeted mice and partially abrogated in mice depleted of IL-4 by neutralizing monoclonal antibodies. (4) IL-10 depletion abrogated the immunosuppressive but not the p36 lymphocyte mitogenic biological effects. (5) The increase in the serum concentrations of both IL-4 and IL-10 were lower in thymectomized than in non-thymectomized mice. (6) The expression of interferon-gamma (IFN-gamma) mRNA was weakly or not at all induced in p36-treated mice. Taken together, these results are in agreement with the promotion of a Th2 immune response induced by p36.