Background: A reflex cough is often observed after an intravenous bolus of fentanyl. This study was conducted to determine whether pre-treatment with intravenous clonidine could effectively attenuate fentanyl-induced cough. Methods: Three hundred ASA I-II patients, aged between 18 and 80 years, undergoing various elective surgeries, were enrolled in this study. All patients were randomly assigned to one of two groups treated with intravenous clonidine 2 μg/kg (clonidine group) or the same volume of normal saline (control group). Intravenous fentanyl (2 μg/kg in 2 s) was injected 2 min after the clonidine or normal saline injection. Changes in the hemodynamics, auditory evoked potentials (AEPs) and Observer Assessment of Alertness/Sedation (OAA/S) rating scale were recorded before and 2 min after the clonidine or normal saline injection and 1 min after the fentanyl injection. The number of coughs 1 min after the fentanyl injection was also recorded. Results: Patients in the clonidine group showed a significantly lower incidence of cough than those in the control group (17.3% vs. 38.7%, respectively; P < 0.01). The blood pressure was lower in the clonidine group than in the control group. There were no significant differences in AEP or OAA/S rating scale. Conclusions: Pre-treatment with intravenous clonidine (2 μg/kg) suppressed the reflex cough induced by fentanyl, with mild hemodynamic changes. Therefore, intravenous clonidine may be a clinically useful method of suppressing fentanyl-induced cough.