Objective of the study is to assess the efficacy of a brief motivational enhancement intervention in adolescents referred to psychiatric treatment who reported substance-use. In a sample of adolescents (n = 237) consecutively admitted to a psychiatry department, 143 were identified as users. Subjects were randomly allocated to one of two groups: an experimental group that received a brief intervention aimed at increasing their awareness of the risks of substance-use, or a control group. All subjects received standard treatment according to the primary diagnosis. Structured questionnaires assessing knowledge, problems, perception of risks and intention of use of psychoactive substances were administered upon admission and 1 month later. Fifty-nine subjects entered the experimental group and 44 the control group. No significant differences between the two groups were identified in socio-demographic features or substance-use. Non-parametric analyses showed a significant increase across time in overall knowledge about drugs and perception of risk in the experimental group (P < 0.05). A significant increase in overall knowledge in the experimental group compared to controls was found (P < 0.05). No differences were observed for other variables such as intention of use or perception of risk. Brief intervention in adolescents entering psychiatric treatment led to a significant change in overall knowledge about psychoactive substances but not in other variables related to use. Our results point to the need of more intensive interventions.