The aim of this study was to compare the effects of 3 inhalation agents that combined with dexmedetomidine infusion on hemodynamic stability and postoperative recovery in patients undergoing supratentorial tumor surgery. After the institute's ethics committee approved this study and written informed consent was obtained from each participant, 90 patients with ASA I and III, who were scheduled for supratentorial tumor surgery, were recruited for this prospective, randomized controlled study. Routine monitoring was applied for unpremedicated patients on arrival in the operating room. All the patients received IV dexmedetomidine 0.5 μg/kg over 10 minutes, followed by 0.9 μg/kg/h infusion during maintenance. Patients were randomly divided into 3 groups. Anesthesia was maintained by sevoflurane in group 1, desflurane in group 2, and isoflurane in group 3. Hemodynamic variables, brain relaxation scores, intraoperative anesthetics requirement, and recovery characteristics were recorded. Demographic values, hemodynamic variables, and brain relaxation scores were similar among the groups. Mean arterial pressure was higher after intubation at the first minute in all groups than at baseline values. Hypertension was reported in 4 of 30 patients in group 1, 8 of 30 patients in group 2, and 5 of 30 patients in group 3, intraoperatively. Eye opening, following the verbal commands, was significantly lesser in patients receiving desflurane-dexmedetomidine than the other groups (P=0.001). We conclude that dexmedetomidine infusion is not sufficient for suppressing hemodynamic responses, decreasing the requirement of inhalation agents, and providing adequate brain relaxation in patients undergoing supratentorial craniotomy. Desflurane-dexmedetomidine anesthesia offers lesser eye opening and a slower response to verbal commands postoperatively.