In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G × E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G × E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17–18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity. © 2007 Wiley-Liss, Inc.