Leak-off pressure is a main factor to induce formation leak-off so that it can be utilized as a crucial parameter to analyze the causation of well leak-off accidents, and that in-depth investigation on leak-off pressure is of vital importance for secure drilling. By analyzing the characteristics of leak-off formation, this paper divides the leak-off into natural leak-off and fractured leak-off, and then defines the conception of minimal leak-off pressure. The leak-off mechanism of fractured formation is investigated. Investigation results show that the currently existent prediction method of fracture pressure is established on the foundations of non-filtration borehole wall assumption as well as the Terzaghi effective stress model. These foundations are not consistent with the practical features of thief formation, which would inevitably cause deviation of calculated results with actualization. Natural leak-off formation constitutes the majority of formation leak-off phenomena. Therefore, it is urgent to build up the leak-off pressure curve instead of fractured pressure curve and take precautions against natural leak-off. The technique of leak-off pressure prediction with fully-coupled 3D natural fracture modeling was applied in the fractured reservoir which located in the northwest of Junggar Basin, China. Case analyses have proved that this lost circulation pressure model is of sufficiency in scientific bases and pertinence. The prediction result derived from the model is relatively consistent with the actual situation and consequently provides a substantial basis for a rational design of the drilling fluid density as well as the leak resistance and sealing. Therefore it is suggested that the design of drilling engineering should take the lost circulation pressure into consideration.