Background: Both preoperative oral dextromethorphan (OM) and IV clonidine attenuates arterial blood pressure and heart rate increases during tourniquet inflation under general anesthesia. Effect of preoperative oral clonidine on these variables was not investig clinically; it seems that clonidine is more effective than OM in blunting of these responses.Materials and methods: We designed this study to compare the effect of preoperative oral OM or clonidine on hemodynamic changes during tourniquet inflation in 75 patients undergoing lower limb surgery under general anesthesia. Patients were randomly assigned into three groups; OM (n=25; OM 30mg), clonidine (n=25; clonidine 3 mg/kg), and control (n=25; placebo) bgroups. Anesthesia was maintained with 1.2%-14% OM, clonidine, or placebo was given orally in a double-blinded fashion ninety minutes before induction of anesthesia.Results: Systolic, diastolic, mean arterial blood pressure (SAP, OAP, MAP), and heart rate (HR) were measured at 0, 30, 45, 60 min after the start of tourniquet inflation, before tourniquet release (BTR), and 20 mins after tourniquet deflation. (20ATR). SAP, OAP and MAP were significantly lower in the clonidine group compared with control after 45, 60 min tourniquet inflation and at BTR (p<0.05). Twenty minutes after deflation, OAP and MAP in the control group was still increased and significantly higher compared with the clonidine group. Development of more than a 30% increase in systolic arterial pressure during tourniquet inflation was more frequent in the control group than the other groups.Conclusion: Preoperative oral clonidine 3 mg/kg significantly prevented tourniquet-induced systemic arterial pressure in patients under general anesthesia better than oral DM.