Depressive disorders are heterogeneous psychiatric disorders involving deficits in cognitive, psychomotor, and emotional processing. Depressive disorders have a significant genetic component, with severe, recurrent and early-onset forms demonstrating elevated heritability. In this study we genotyped eleven single nucleotide polymorphisms (SNPs) spanning the estrogen receptor alpha gene (ESR1) in a large family-based childhood-onset mood disorder (COMD) sample. None of the individual SNP or global haplotype analyses was significant in the entire COMD sample, but haplotype analysis of three SNPs in strong linkage disequilibrium (rs746432, rs2077647, and rs532010) uncovered an association with COMD, specifically in females. Our data are consistent with previous studies demonstrating a female-specific association between ESR1 and neurobehavioral phenotypes. These results suggest the existence of sex-specific etiological factors in depressive disorders, related to estrogen, with onset in childhood.