Abstract: Accurate prediction of the annular frictional pressure drop under eccentric rotation of drill string is an important theoretical basis for managed pressure drilling (MPD) in complex structure wells. However, the conventional calculation methods for the annular frictional pressure drop of drilling fluid cannot be directly applied to calculating the annular frictional pressure drop in complex structure wells. For this reason, the influences of eccentricity (0−67.42%) and the rotational speed (0−114.65 r/min)of the drill string on the frictional pressure drop gradient in a typical annulus (created by a ϕ127.0 mm drill pipe and a ϕ215.9 mm wellbore) were analyzed. The results show that when the eccentricity is lower than 45.00%, the rotational speed and eccentricity have a weak influence on the frictional pressure drop gradient. Specifically, the frictional pressure drop gradient decreases slightly with the increase of rotational speed but increases with the increase of eccentricity; when the eccentricity is higher than 45.00%, the frictional pressure drop gradient decreases with the increase of eccentricity at low rotational speed（<60 r/min）, and the friction pressure drop gradient increases slightly with the increase of eccentricity at high rotational speed (>60 r/min). According to the numerical simulation results, a dimensionless frictional pressure drop gradient prediction model with eccentricity classification was built. The equivalent circulating density (ECD) of ϕ215.9 mm section of a horizontal well in the South China Sea was calculated by the proposed model. The results were then compared with the pressure-while-drilling (PWD) test results, with an average relative error of 0.45%, indicating that the proposed model has favorable accuracy. This study concludes that the proposed calculation model of the dimensionless annular frictional pressure drop under eccentric rotation can precisely describe the annular pressure field and ECD, and provide guidance for the hydraulic parameter optimization of MPD.