In the present study, we evaluated whether lymphocyte cytokine production during human and rat pregnancy shifts toward T helper cell type 2 (Th2) cytokine production. Therefore, blood samples were taken during the follicular and luteal phase and during pregnancy in rats and humans. Whole blood was ex vivo-stimulated with phorbol 12-myristate 13-acetate and calcium ionophore and intracellular interferon-gamma (IFN-gamma) and interleukin (IL)-4 production, and the percentage of cells in the various lymphocyte populations was measured using flow cytometry. Rats and humans adapted their immune responses to pregnancy but have different strategies: During human pregnancy, the percentage of lymphocytes producing IFN-gamma was decreased, and the percentage IL-4-producing lymphocytes was not affected. The rat adapts its immune response to pregnancy by decreasing the total number of the various lymphocyte populations, and the percentage of IFN-gamma- or IL-4-producing lymphocytes was not affected or increased (% IFN-gamma-producing cytotoxic lymphocytes). It is speculated that during rat pregnancy, there is no need to decrease the number of IFN-gamma-producing lymphocytes, as in nonpregnant rats, the total number of IFN-gamma-producing lymphocytes after stimulation is relatively low, and there is no necessity for a further decrease. In nonpregnant humans, the percentage IFN-gamma-producing lymphocytes is much higher and probably dangerous for pregnancy, and therefore, this percentage needs to decrease during pregnancy. In conclusion, although the data from humans concur with the Th1/Th2 paradigm, the data from rats do not concur with this paradigm. The present studies therefore challenge the classical Th1/Th2 paradigm during pregnancy.