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Substance abuse is the result of interaction between constitutional, environmental and socio-demographic factors. Several studies have been demonstrated that the adolescent substance abuse is a serious and growing problem. The aim of our study is to investigate the association between substance, alcohol and tobacco abuse and socio-familiar factors, to evaluate a substance abuse prevention program which decreases substance use in adolescents. A cross-sectional survey was developed and carried out by involving a group of adolescents, randomly selected from the secondary school of Teramo province. Data were collected by a self-administered questionnaire. The associations between substance use and the determinants taken into account was evaluated by the chi-square test of Fisher exact test or trend test when appropriated. Our data show that the alcohol abuse is more frequent in males (41.1%, p = 0.000), while the nicotine abuse is more frequent in females (46.1%, p = 0.005). However, our results show that the abuse of alcohol, nicotine, heroine, cocaine and ecstasy is associated to lack of stability in the family, respectively: 61.5% (p = 0.001); 61.5% (p = 0.022); 7.7% (p = 0.018); 7.7% (p = 0.010): 7.7% (p = 0.004). The nicotine abuse is higher in adolescents living with a smoker: 50.3% (p = 0.000). Finally, the substance abuse is higher in adolescents having friends that are drug-addicts, in particular: alcohol 49.6% (p = 0.000), nicotine 43.0% (p = 0.000), cannabis 27.9% (p = 0.000). This survey suggests that the knowledge of factors influencing the initiation, combination and cessation of the use of substance is crucial for the prevention of drug use among adolescents.