Background: Both genetic and psychosocial risk factors influence the risk for depression in development. While the impacts of family structure and of serotonergic polymorphisms upon individual differences for affective problems have been investigated separately, they have never been considered together in a gene-environment interplay perspective. Methods: We examined the effects of family structure and two serotonergic polymorphisms (the TPH2 G-703T and the 5-HTTLPR) upon depressive symptoms assessed by the new CBCL/6-18 DSM-oriented Affective Problems scale in a general population sample of 607 Italian children aged 10-14 years. Results: Belonging to "one-parent" families, the TPH2 G-703T "G variant", and the 5-HTTLPR "short" alleles were associated--both alone and in apparent gene-by-environment interaction--with higher Affective Problems scores. As predicted by quantitative genetics theory, both polymorphisms contributed with a small effect size, while "family structure" had a moderate effect size. Conclusions: A putative hazard factor impinging on individual risk at the family-wide level, namely family structure, appears to act interactively with two pivotal serotonergic genes in heightening risk for Affective Problems. Although it remains to be demonstrated that belonging to a one- rather than a two-parent family has true environmental causal effects on Affective Problems, these data may contribute to identify/prevent risk for depression in childhood.