Many of the factors affecting susceptibility to dental caries are likely influenced by genetics. In fact, genetics accounts for up to 65% of inter-individual variation in dental caries experience. Sex differences in dental caries experience have been widely reported, with females usually exhibiting a higher prevalence and severity of disease across all ages. The cause for this sex bias is currently uncertain, although it may be partly due to the differential effects of genetic factors between the sexes: gene-by-sex interactions. In this family based study (N = 2,663; 740 families; ages 1-93 years), we assessed dental caries via intra-oral examination and generated six indices of caries experience (DMFS, dfs, and indices of both pit-and-fissure surface caries and smooth surface caries in both primary and permanent dentitions). We used likelihood-based methods to model the variance in caries experience conditional on the expected genetic sharing among relatives in our sample. This modeling framework allowed us to test two lines of evidence for gene-by-sex interactions: (1) whether the magnitude of the cumulative effect of genes differs between the sexes, and (2) whether different genes are involved. We observed significant evidence of gene-by-sex interactions for caries experience in both the primary and permanent dentitions. In the primary dentition, the magnitude of the effect of genes was greater in males than females. In the permanent dentition, different genes may play important roles in each of the sexes. Overall, this study provides the first direct evidence that sex differences in dental caries experiences may be explained, in part, by gene-by-sex interactions.