Abstract Adolescents often take ethanol (EtOH) in combination with MDMA (3,4-methylenedioxymethylamphetamine). In the present work we studied the effect of repeated intermittent adolescent pre-exposure to both drugs on the behavioral and neurochemical effects of MDMA in mice. Sixteen days after pre-treatment, the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm were evaluated, along with the levels of biogenic amines, basal motor activity and corticosterone response to different challenges. Pre-exposure to EtOH, MDMA or EtOH+MDMA did not affect the CPP induced by 10mg/kg of MDMA. However, adolescent exposure to EtOH or MDMA increased the duration of the conditioned rewarding effects of MDMA. Following extinction of the CPP, a priming dose of 5mg/kg of MDMA elicited reinstatement in all the groups, with the duration of this reinstated CPP being longer in mice pre-treated with MDMA. After reinstatement, an increase in monoamine levels was observed in mice pre-exposed to EtOH (DA, DOPAC and 5-HT in the striatum and 5-HIAA in the cortex and hippocampus) or MDMA (5-HT in the hippocampus). Basal motor activity and basal levels of corticosterone were not affected by any of these pre-treatments, but the group pre-exposed to MDMA showed higher levels of corticosterone in response to the administration of 10mg/kg of MDMA. Behavioral and hormonal effects of adolescent exposure to MDMA were reversed by co-administration of EtOH. Our results suggest that exposure to EtOH or MDMA during adolescence prolongs the rewarding properties of MDMA.