Because the causes of conotruncal cardiac defects are poorly understood, a case-control study was conducted to investigate maternal risk factors for conotruncal cardiac defects. Eligible cases included all infants who were born from 1976 through 1980 to residents of the five county metropolitan Atlanta area and diagnosed with truncus arteriosus, transposition of the great arteries or tetralogy of Fallot. Eligible control infants were a sample of comparable infants without birth defects. Maternal interviews were conducted for 73% (83 of 114) of eligible cases and 72% (1,303 of 1,804) of eligible control infants. The results showed increased risks associated with maternal diabetes (odds ratio 5.6; 90% confidence interval 2.5 to 15.6), maternal stress related to job loss, divorce, separation or death of a close friend or relative (odds ratio 2.4; 90% confidence interval 1.4 to 4.2) and a history of a sibling with a cardiac defect (odds ratio 4.8; 90% confidence interval 2.2 to 10.5). The statistical power of the data was adequate to rule out threefold or greater increases in risk for a wide variety of other exposures, including maternal illnesses other than diabetes, contraceptive use, nonmedicinal drugs (for example, coffee, tea, alcohol, cigarettes, street drugs), employment and education. This population-based study offers no clues that could explain either the high rate of transposition of the great arteries or the temporal trend of an increasing rate of tetralogy of Fallot in Atlanta.