The augmentation of methotrexate-induced embryotoxicity by aspirin was studied. Pregnant Charles River CD rats were given methotrexate or aspirin alone or in combination on gestation day 9 or 12. The frequency of fetal abnormalities was not affected and fetal body weight loss was not additive in the combined treatment. However, pretreatment with aspirin (200 mg/kg) significantly enhanced the embryolethality of methotrexate given at doses of 0.2 mg/kg on day 9 and 1.5 mg/kg on day 12. Studies with tritiated methotrexate in pregnant rats demonstrated that aspirin delayed the renal excretion of methotrexate and increased the concentrations of methotrexate in maternal plasma and the embryos. It is suggested that these effects are responsible for the observed potentiation of embryolethality.