The toxic interaction of caffeine and phenytoin during pregnancy was investigated in mice of the ICR strain on E10 of gestation. Caffeine, over a range of dosages, showed limited embryotoxic activity. Phenytoin was also weakly teratogenic and dosages needed to elicit embryotoxicity were accompanied by a significant increase in maternal lethality. Pretreatment with caffeine enhanced phenytoin-induced toxicity and teratogenicity and these observations confirm that caffeine has the ability to function as a coteratogen. Pretreatment with phenytoin produced a significant increase in maternal lethality following caffeine administration but no co-teratogenic effect. It is suggested that these results are the consequence of a yet undefined interaction at critical receptor sites in the maternal-embryo unit.