This study examined the relationship between maternal tobacco and alcohol consumption during the first trimester of pregnancy and oral clefts. Data were derived from a European multicenter case-control study including 161 infants with oral clefts and 1134 control infants. Multivariate analyses showed an increased risk of cleft lip with or without cleft palate associated with smoking (odds ratio [OR]= 1.79, 95% confidence interval [CI]= 1.07, 3.04) and an increased risk of cleft palate associated with alcohol consumption (OR= 2.28, 95% CI= 1.02, 5.09). The former risk increased with the number of cigarettes smoked. This study provides further evidence of the possible role of prevalent environmental exposures such as tobacco and alcohol in the etiology of oral clefts.