AbstractGlucocorticoids cause cleft palate in sensitive mouse strains by interfering with the proliferation of mesenchymal cells in the palatal shelves; 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) also causes cleft palate, but its effects involve the epithelial cells. The purpose of this study was to examine the interaction of TCDD and the glucocorticoid hydrocortisone in the induction of malformations. Pregnant C57BL/6N mice were treated on gestation days 10–13 with TCDD (0 or 3 μg/kg, p.o.), hydrocortisone (0, 25, 50, or 100 mg/kg, s.c.) or a combination of TCDD and hydrocortisone. The dams were killed on gestation day 18 and the mice were analyzed for maternal and fetal toxicity and soft tissue malformations. TCDD alone had no effect on litter size, fetal weight or viability, or maternal weight gain. This dose of TCDD is essentially a threshold dose and it did not produce cleft palate in this study, but all the TCDD‐treated fetuses had hydronephrosis, the most sensitive indicator of TCDD teratogenicity. Hydrocortisone alone caused dose‐related decreases in fetal weight and maternal liver/body weight ratios, and dose‐related increases in cleft palate (0, 5, 10, and 30%). No effects of hydrocortisone were detected on litter size or fetal viability, but maternal weights were affected. Combination of all doses of hydrocortisone with TCDD resulted in a 100% incidence of cleft palate, accompanied by a decrease in litter size and fetal weight and an increase in fetal mortality related to the dose of hydrocortisone. TCDD tended to reverse the decrease in liver/body weight ratio seen with hydrocortisone alone. Morphological assessment of the palatal shelves late on gestation day 14 revealed that the embryos exposed to both TCDD and hydrocortisone resembled hydrocortisone alone. The synergism observed between these two teratogens may be due to changes in the receptors which mediate sensitivity to the induction o