Abstract: The main aim of this study was to evaluate the effects of dextromethorphan and midazolam and their combination on morphine tolerance and dependence in mice. In the present study, different groups of mice were rendered randomly and received morphine (50 mg kg-1, s.c.), morphine (50 mg kg-1, s.c.) + Dextromethorphan (25, 50 and 75 mg kg-1, i.p.), morphine (50 mg kg-1, s.c.) + midazolam (0.5, 1 and 2 mg kg-1, i.p.), morphine (50 mg kg-1, s.c.) + [Dextromethorphan (25 mg kg-1, i.p. ) + midazolam (0.5 mg kg-1, i.p.)] once a day for four days. Tolerance was assessed by administration of morphine (9 mg kg-1, i.p.) on fifth day. Withdrawal symptoms (markers for dependence) was assessed by administration of naloxone (4 mg kg-1, i.p.) 2 h after co-administration of morphine with either Dextromethorphan or midazolam or their combination. Results showed that pretreatment with Dextromethorphan or midazolam decreased the degree of tolerance and withdrawal symptoms significantly. Additionally co-administration of Dextromethorphan and midazolam couldn`t decreased the tolerance and dependence significantly. From these results it may concluded that Dextromethorphan and midazolam alone or in combination could prevent the development of morphine induced tolerance and dependence. These effects can be related to the N-Methyl-D-Aspartate (NMDA) receptor antagonist behavior of Dextromethorphan and GABA-receptor agonist property of midazolam.