[show abstract][hide abstract] ABSTRACT: Introduction: Effects of cimetidine (CIM) on locomotor is controversial. This study was designed to evaluate the effects of CIM on motor activity and possible roles of opioid receptors in CIM-induced decrement in locomotor activity in mice. Materials & Methods: Thirty-six male mice (25-30gr) were divided into six groups in this study. Locomotor activity was evaluated using an automated activity monitor system. CIM (50 mgkg, i.p.) was injected 25 min before testing in presence or absence naloxone (2 mg/kg, sc). Morphine (5 mg/kg, i.p) was injected 25 min before testing in the presence or absence CIM. decreased motor activity significantly. Pretreatment of or morphine did not change CIM – induced response significantly. Results: The results showed that CIM significantly decreased motor activity in mice (P=0.000). Pretreatment of nalxone did not change CIM-induced response significantly. Morphine alone did not change motor activity. Pretreatment of CIM did not change morphine-induced response. Conclusion: Data indicated that cimetidine can reduce motor activity independence from interaction with opioid receptors.