Cystic fibrosis is the most common fatal autosomal recessive disease affecting Caucasian populations. It remains a puzzle how this disease is maintained at such a remarkably high incidence, however, it could be due to a reproductive advantage in cystic fibrosis heterozygotes. We tested this hypothesis. An adult Danish general population sample of 9141 individuals was screened for cystic fibrosis ΔF508 heterozygotes; 250 carriers of this mutation were identified (2.7%). In the total sample ΔF508 heterozygotes did not have more children than noncarriers; however, smoking interacted with genotype in predicting number of children (ANOVA:P <0.001). Among nonsmokers, heterozygotes had more children than noncarriers (Wilcoxon: P = 0.03). Among smokers, the opposite was found: heterozygotes had fewer children than noncarriers (Wilcoxon: P = 0.001). These findings remained significant after allowing for gender and the potential confounders of age, income, and education. Finally, after allowing for these covariates, number of children in ΔF508 heterozygotes decreased with increasing extent of smoking (trend test: P = 0.003), while the opposite was true for noncarriers (trend test: P <0.001). In conclusion, overall these results do not support a reproductive advantage for cystic fibrosis ΔF508 heterozygotes. However, the data cannot totally exclude the possibility that nonsmoking ΔF508 heterozygotes experience a reproductive advantage while smoking ΔF508 heterozygotes experience the opposite, a reproductive disadvantage. Accordingly, the data suggest a previously undocumented role of smoking on fecundity among cystic fibrosis heterozygotes.