BACKGROUND: A previous study observed that women who are underweight prior to conception were significantly more likely to have infants affected by congenital diaphragmatic hernia (CDH). The objective of the current study was to examine the association between maternal body mass index and the risk of a CDH-affected offspring based on a larger number of cases of CDH. METHODS: A case control study was conducted using data collected by the Boston University Slone Epidemiology Center Birth Defects Study, which identifies infants with major malformations who are born in the metropolitan area surrounding Boston, Massachusetts; Philadelphia, Pennsylvania; and Toronto, Ontario, Canada. Control infants were selected from infants without malformations who were born in the same areas. The study included 85 cases of CDH and 655 controls delivered between 1993 and 1997. RESULTS: After adjustment for maternal education and maternal age, we observed that women who were thin or underweight for their height (body mass index ≤ 19.0 kg/m2) had an increased risk of having an infant with isolated CDH (OR = 1.9; 95% CI = 0.92-4.1), but no increase in the risk of having a CDH infant with multiple defects (OR = 0. 86; 95% CI = 0.29-2.6) compared with all other women. CONCLUSIONS: Although our finding for isolated CDH was not statistically significant (P = 0.08), it suggests that the offspring of thin or underweight women may have an increased risk of isolated CDH. This finding requires confirmation. If it is confirmed, further research on factors associated with being underweight should be explored such as diet, exercise, and use of drugs. © 2003 Wiley-Liss, Inc.