In a case-control (N = 1427 and 3001, respectively) study of deliveries in Connecticut the incidence of congenital malformations was 52 per 1000 live births. Of all mothers, 44.5% used at least 1 prescribed drug during pregnancy. Case mothers were more likely than controls to have used a prescription drug (odds ratio [o] = 13, P less than .0001), particularly an antidepressant (o = 7.6), narcotic analgesic (o = 3.6), or tranquilizer (o = 23); P less than .01 for all associations. There was a synergistic relationship with tranquilizer use and smoking in pregnancy, resulting in a o = 3.7 (P less than .01) risk for those exposed to both. The synergistic relationship of tranquilizers-cigarettes with malformations supports existing pharmacologic research and suggests that epidemiologic study of the impact of simultaneous maternofetal exposure to environmental agents may further explain the etiology of some congenital malformations.