The hypotheses of (1) gene x environment interaction in the susceptibility to experiment with drugs and (2) hypothalamus-pituitary-adrenal (HPA) axis involvement in mediating the effects of early adverse experiences and gene variants affecting serotonin function on substance abuse vulnerability were tested by investigating in 187 healthy adolescents the possible relevance of 5-HTT "S" polymorphism, childhood parental neglect reported retrospectively and HPA axis function to the susceptibility to experiment with illicit drugs. Higher frequency of the 5-HTT SS genotype seems to be associated with an increased susceptibility to use illegal psychotropic drugs among the adolescents. At the same time, reduced maternal care perception was found to represent a key intermediate factor of the association between SS polymorphism and drug use, suggesting that genetic factors and parental behavior concur to drug use susceptibility. Our results also confirm the relationship between basal plasma levels of cortisol and adrenocorticotropic hormone (ACTH) on the one hand, and retrospective measures of neglect during childhood: the higher the mother and father neglect CECA-Q scores, the higher the plasma levels of the two HPA hormones. Such positive relationship has been proved to be particularly effective and important when associated to the S-allele, both in homozygote and heterozygote individuals. However, when tested together with genotype and parental neglect, the effect of HPA hormones such as cortisol and ACTH was not found to improve significantly the explanatory power of the risk model.