Clinical and experimental evidence has indicated that the maternal immune response is biased toward antibody production and away from cell-mediated immunity during pregnancy, especially in the vicinity of the fetoplacental unit. Because antibody responses are often associated with the Th2 cytokine pattern, this suggests that Th2-type cytokines might predominate locally in the regulation of the maternal immune response. In order to test this hypothesis, we examined the local and distal release of cytokines during murine pregnancy using ELISA assays. We report here that the Th2-specific cytokines IL-4, IL-5, and IL-10 were readily detectable in cell supernatants derived from fetal-placental units in all three trimesters of gestation. IL-3 was also present. These cytokines were detected in lysates of freshly isolated, day 12 decidual and placental cells, and in supernatants as early as 15 min after the beginning of culture. The presence of functional IL-10 was confirmed by specific bioassay. IL-10 mRNA was localized to the decidua at day 6 of gestation by in situ hybridization. IFN-gamma was also found in the supernatants from the first trimester of pregnancy, but was barely detectable in the second, and undetectable in the third trimester. Cytokine expression was consistently detected in samples from individual mice. None of these cytokines was produced by unstimulated spleen or mesenteric lymph nodes from pregnant mice. IL-4, IL-10, and IFN-gamma were produced by Con A-stimulated spleen cells from virgin mice, but in ratios opposite to those found in the placenta. These observations indicate that Th2-specific cytokines are normally produced at the maternal-fetal interface. The continuous presence of IL-4, IL-5, and IL-10, with early and transient expression of IFN-gamma, can provide a molecular basis for the antibody/Th2-like bias of the maternal immune response during pregnancy.