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Several previous studies suggest that maternal stress may be associated with increased risk of certain birth defects. This study examined the association of maternal stressful life events with risks of several birth defects.The data are from a recent, population-based case-control study. Telephone interviews were conducted with 1355 eligible case mothers and 700 control mothers. Maternal stress was measured by responses to 18 yes/no questions about life events that occurred from 2 months before through 2 months after conception.An increase in the stressful life events index (ie, number of “yes” responses to the 18 life-events questions) was associated with increased risk of cleft palate, cleft lip with or without cleft palate, d-transposition of the great arteries, and tetralogy of Fallot, after adjustment for maternal race-ethnicity, education, obesity, age, smoking, drinking, intake of folic acid-containing supplements, neighborhood crime, and food insecurity. For example, the odds ratio for a 3-unit change in the stress index was 1.45 (95% confidence interval = 1.03–2.06) for cleft palate. Increased stress was associated with an increased risk of spina bifida and anencephaly particularly among women who did not take folic acid supplements. A 3-unit change in stress was associated with a 2.35-fold increased risk of anencephaly among women who did not take supplements (CI =1.47–3.77) and a 1.42-fold increased risk among women who did (CI = 0.89–2.25).The adverse health effects of stress may include increased risks of certain birth defects.