Abstract: In the late development periods of many oil and gas fields, reservoir pressure decreased to depletion, and the pressure coefficient would be reduced less than 0.4. Formation pressure reduction would result in in-situ stress changes and cause the influence on wellbore stability in drilling. Based on the influence of pressure depletion on reservoir in-situ stress and stress distribution around the wellbore in depleted reservoir, this paper analyses the effect of pressure depleted on wellbore stability of directional wells. Calculation results shows that there is a neutral angle in depleted reservoir drilling, when inclination angle is smaller than the neutral angle, the safety window of drilling fluid density will become wider, and when inclination angle is larger than the neutral angle, the safety window of drilling fluid density will become narrower. The neutral angle has no relationship with the level of pressure depleted, but has relationship with azimuth angle, and keep inclination angle below the neutral angle and away from the azimuth of maximum horizontal principle stress is beneficial to drilling safety. It provides a reference for drilling designing in depleted reservoirs of different periods.