This study was designed to evaluate the effect of tracheal topical anesthesia using EMLA® Cream (EC) coated on the endotracheal tube (ETT) with or without epidural anesthesia (EA) on isoflurane requirement during general anesthesia (GA) and investigate whether EC coated on the ETT with EA was associated with the additive effect compared with the effect when each anesthetic was administered independently. The prospective randomized, double-blinded, and controlled study included 60 ASA I-II patients scheduled for upper abdominal surgery requiring GA. Patients were randomly assigned to one of the following groups: group 1 received GA, group 2 received EC + GA, group 3 received GA + EA, and group 4 received EC + GA + EA. Isoflurane was administered at the required concentrations to maintain the mean arterial pressure at a level not exceeding 20% of preoperative values. The percentage mean expired concentration (%MEC) was used in calculating the isoflurane requirement. Emergence agitation, postoperative sore throat, and hoarseness were recorded. Groups 2, 3, and 4 exhibited a significant reduction on isoflurane requirement compared with group 1 (P < 0.05). The isoflurane requirement evaluated by %MEC decreased by 12%, 38%, and 50% in groups 2, 3, and 4, respectively. The incidence of emergence agitation was significantly lower in groups 2 and 4 than those in groups 1 and 3 (P < 0.05). Tracheal topical anesthesia using EC coated on ETT with or without EA reduced the isoflurane requirement during GA, indicating that EC combined with EA exhibited an additive effect on the requirement of general anesthetic.