Objective To study the influence of a possible interaction between maternal smoking and high body mass index (BMI) on the occurrence of specific congenital heart anomalies (CHA) in offspring. Design Case-control study. Setting Data from a population-based birth defects registry in the Netherlands. Patients Cases were 797 children and fetuses born between 1997 and 2008 with isolated non-syndromic CHA. They were classified into five cardiac subgroups: septal defects (n = 349), right ventricular outflow tract obstructive anomalies (n = 126), left ventricular outflow tract obstructive anomalies (n = 139), conotruncal defects (n = 115) and other CHA (n = 68). Controls were 322 children and fetuses with chromosomal anomalies without cardiac anomalies. Main outcome measures Investigation of whether an interaction between maternal smoking and high BMI influences the occurrence of CHA in offspring by calculation of the synergy factors and 95% CIs. Results As opposed to smoking or high BMI alone, the risk for CHA in the offspring of women with high BMI (>= 25 kg/m(2)) who also smoked was significantly increased. The adjusted OR was 2.65 (95% CI 1.20 to 5.87) for all CHA, 2.60 (95% CI 1.05 to 6.47) for septal defects and 3.58 (95% CI 1.46 to 8.79) for outflow tract anomalies. The interaction between maternal high BMI and smoking contributed significantly to the occurrence of all offspring-CHA combined, and to the occurrence of all cardiac subgroup anomalies except right ventricular outflow tract obstructive anomalies. Conclusions Maternal overweight and smoking may have a synergistic adverse effect on the development of the fetal heart. Overweight women who wish to become pregnant should be strongly encouraged to stop smoking and to lose weight