The sitting position may cause significant hemodynamic instability and cerebral hypoperfusion. We investigated the effects of desflurane and propofol on regional cerebral oxygenation (rSO2) in the sitting position during arthroscopic shoulder surgery. Forty patients undergoing arthroscopic shoulder surgery in the sitting position were randomly allocated to the desflurane group (n = 20) or the propofol group (n = 20). Anesthetic agents were maintained and adjusted with the effect-site concentration of propofol (2-3.5 μg/ml) or desflurane (4-7 vol%) to obtain a bispectral index (BIS) of 40-50. The hemodynamic variables, end-tidal carbon dioxide tension (ETCO2) and rSO2 were measured and evaluated. There were no differences in BIS, hemodynamic variables and ETCO2 between the groups. The rSO2 values in the desflurane group were higher compared to the propofol group at 3, 5, 7 and 9 min after the sitting position (P = 0.031, 0.047, 0.025 and 0.034, respectively). However, it decreased significantly from the baseline values at 3, 5, 7 and 9 min after the sitting position in both groups (P < 0.001). The change in rSO2 across time was not significantly different between the groups (P = 0.183). The incidence of rSO2 <75% of the baseline values after the sitting position was similar between the groups (0 and 10% in the desflurane and propofol group, respectively, P = 0.487). When anesthetized patients were raised to the sitting position, desflurane preserved cerebral oxygenation better than propofol at equipotent concentrations in terms of BIS. However, both anesthetics were associated with significant decrease in the rSO2 values during the sitting position.