In threatening environments, the short (S) allele of 5-HTTLPR is proposed to augment risk for depression. However, it is unknown whether 5-HTTLPR variation increases risk for depression in environments of deprivation, lacking positive or nurturant features. Two independent longitudinal studies (n = 681 and 176, respectively) examined whether 5-HTTLPR moderated associations between low levels of positive parenting at 11-13 years and subsequent depression at 17-19 years. In both studies only LL homozygous adolescents were at greater risk for depression with decreasing levels of positive parenting. Thus, while the S allele has previously been identified as a susceptible genotype, these findings suggest that the L allele may also confer sensitivity to depression in the face of specific environmental challenges.