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Prepregnant obesity has been shown to be related to several birth defects, most notably neural tube defects. We investigated the previously observed association between obesity and spina bifida and also possible associations between obesity and other birth defects.We conducted a case-control study of fetuses and liveborn infants among California births, July 1999 and June 2004. Of those eligible, 80% of case mothers (n = 659) and 77% of control mothers (n = 700) were interviewed. Cases were 147 infants with anencephaly, 191 with spina bifida, 142 with d-transposition of great arteries, and 181 with tetralogy of Fallot. Maternal body mass index (BMI) was based on prepregnant weight and height.The odds ratios of birth defects with obesity (BMI ≥30 relative to normal BMI) were 1.6 for anencephaly (95% confidence intervals = 1.0–2.6); 1.4 for spina bifida (0.8–2.2); 0.7 for d-transposition of great arteries (0.4–1.4); and 0.8 for tetralogy of Fallot (0.4–1.4). Modestly elevated odds ratios were observed with obesity among women who reported weight gain in their waist before pregnancy—for anencephaly, 2.4 (1.2–5.1) and for spina bifida, 1.8 (0.9–3.6).These data do not fully support earlier findings with respect to the relationships of obesity with anencephaly and spina bifida.