Reports suggest that when prospective mothers take supplemental multivitamins containing folic acid during the periconceptional period, the risk of a neural tube defect declines and some types of congenital cardiac defects may be less frequent. This population-based case-control study examined the relation, if any, between maternal multivitamin use and the risk of cardiac defects. Data are from the Atlanta Birth Defects Case-Control Study, in which information was obtained from parents of infants with and without birth defects who were born between 1968 and 1980. The participation rate was 71%, leading to 958 case infants having nonsyndromic cardiac defects and 3029 control infants lacking birth defects of any kind. Infants whose defects were of known genetic or teratogenic origin were excluded. The data source was a stratified random sample of birth certificates.Septal defects, obstructive conditions, and outflow tract abnormalities were most prevalent. Mothers of control infants were more likely to be white and to have delivered in the earlier years of the period under study. Mothers of case infants were likelier to have had a chronic disorder of some kind around the time of conception. Regular use of multivitamins during the periconceptional period was reported by 14.2% of case mothers, whereas another 38.9% reported no such use. Periconceptional use of multivitamins seemed to lower the risk of all heart defects combined by 24% (odds ratio = 0.76, 95% confidence interval = 0.60–0.97). The major differences were a 54% reduction in outflow tract defects and 39% fewer ventricular septal defects. No protection was apparent when mothers started taking multivitamins in the second or third trimester. Should this apparent relationship prove to be causal, approximately one in four major cardiac defects might be prevented by making sure that prospective mothers take multivitamins during the periconceptional period.