Several studies have shown that the prevalence of ventricular septal defects (VSDs) has increased significantly in the United States in the past 30 years. This increase has been primarily attributed to increased detection through echocardiography. However, little is known about the etiology of VSD. This study sought to evaluate the association between maternal lifestyle exposures and the risk for VSD in offspring. The Atlanta Birth Defects Case-Control Study was used to identify 122 isolated simple VSD cases and 3029 control infants born during the period 1968 through 1980 in the metropolitan Atlanta area. Exposure data on alcohol, cigarette, and illicit drug use were obtained through standardized interviews with mothers and fathers. Associations between lifestyle factors and VSD were calculated using maternal self-reports; associations were also calculated using paternal proxy-reports of the mother's exposures. Maternal self-report of heavy alcohol consumption and paternal proxy-report of the mothers' moderate alcohol consumption were associated with isolated simple VSD. A two-fold increase in risk of isolated simple VSD was identified for maternal self- and paternal proxy-reported cannabis use. Risk of isolated simple VSD increased with regular (three or more days per week) cannabis use for both maternal self- and paternal proxy-report, although the association was significant only for maternal self-report. This is the first study to identify an association between maternal marijuana use and VSD in offspring. Further studies are needed to elucidate this association.