We carried out a retrospective investigation on the effect of obesity on dexmedetomidine (DEX) requirements when administered with fentanyl (FEN) during mechanical ventilation after major surgeries. After Institutional Review Board approval, 14 obese patients with a body mass index (BMI) ≥ 30 kg/m(2) and the same number of non-obese patients with similar backgrounds to the obese patients were selected from medical records. Doses of DEX in the first 48 h or until the end of sedation or extubation were calculated for comparison. In addition to comparison of dosing between the groups, associations between total body weight (TBW), BMI, and lean body mass (LBM) values and doses of DEX (mcg/h), between BMI and various indices (i.e., amount per TBW per hour and amount per LBM per hour) of DEX doses, and between above indices of DEX and FEN doses were also examined. There were no significant differences in DEX dose indices between the groups. However, DEX requirements (mcg/h) were significantly increased with TBW (kg) (r = 0.51, P = 0.003), BMI (r = 0.49, P = 0.006) and LBM (kg) (r = 0.42, P = 0.02), which might have enhanced the DEX metabolism with physiological changes with obesity. These findings will be beneficial for future clinical pharmacological analysis of DEX.