To estimate whether obese women have an increased risk of orofacial clefts in their offspring, compared with average-weight women. The study was based on information on maternal body mass index (BMI) collected in early pregnancy and on the existence of orofacial clefts in the offspring, ascertained from multiple sources. The study included 1686 women who had infants with an orofacial cleft and as controls all delivered women (n = 988,171) during the study period, 1992 through 2001. Infants with chromosome anomalies were excluded. The women were divided into underweight (BMI <19.8), average weight (reference group, BMI 19.8 to 26), overweight (BMI 26.1 to 29), and obese (BMI >29). Adjustments were made for year of birth, maternal age, parity, and maternal smoking. Obese (BMI >29) mothers had an overall increased risk for having an infant with orofacial clefts: odds ratio 1.30 (95% confidence interval 1.11 to 1.53). This increased risk was higher when the cleft was associated with other major malformations than when it was isolated. There was no statistically significant difference between the risk estimates for cleft lip and cleft palate. In this large sample, a positive association appears between maternal obesity in early pregnancy and orofacial clefts in the offspring. The explanation for this association is not known, but a relationship with undetected type 2 diabetes is one possibility.