Anesthesia with desflurane and remifentanil can be maintained with either fixed or titrated desflurane concentration. We hypothesized that the fixed-gas concentration (FG) method would reduce the number of anesthetic titrations without hypnotic and hemodynamic instability compared to the bispectral index (BIS)-guided (BG) method. Forty-eight patients were randomly allocated to the FG or BG groups. In the FG group, desflurane vaporizer setting was fixed at 1 age-corrected minimum alveolar concentration (MAC). In the BG group, desflurane was titrated to target a BIS level at 50. Remifentanil was titrated to maintain a systolic arterial pressure (SAP) of 120 mmHg in both groups. Our primary endpoint was the hypnotic stability measured by the wobble of BIS in performance analysis, and the secondary endpoints included the wobble of SAP, mean BIS value during surgery, and the number of anesthetic titrations. The BIS in the FG group showed significantly less wobble (3.9 ± 1.1% vs 5.5 ± 1.5%, P <0.001) but lower value (33 ± 6 vs 46 ± 7, P <0.001) than BG group. The wobble of SAP showed no difference between groups [median (inter-quartile range), 5.0 (4.1-7.5)% vs 5.2 (4.2-8.3)%, P = 0.557]. The numbers of anesthetic titrations in the FG group were significantly lower than the BG group (0 ± 0 vs 8 ± 5, P<0.001 for desflurane, 13 ± 13 vs 22 ± 17, P = 0.047 for remifentanil). Less wobble in BIS and reduced anesthetic titration without hemodynamic instability during the FG technique may be practical in balanced anesthesia using desflurane and remifentanil anesthesia. Clinical trial: This study was registered at ClinicalTrials.gov (NCT02283866).