Abstract: It is difficult to control the wellbore pressure while running casing in oil and gas wells with negative pressure windows, which are inclined to cause complex accidents such as overflow or leakage. The calculation models of the slurry column structure and wellbore pressure during managed pressure casing running were established on the basis of multi-density gradient drilling fluids in wells and the theory of transient fluctuating pressure. With the key exploration well Letan-1 of CNPC as an example, the variation of the slurry column structure in the process of running casing and drilling fluid circulation was simulated and calculated. In addition, the corresponding drilling fluid circulation scheme in the casing running process was provided, and the rate of running casing and the managed pressure value of the well head at different stages were recommended. The results demonstrate that 1) the leakage prevention and pressure stability in the wellbore with the negative pressure window are achieved after drilling through the optimized multi-density gradient drilling fluid; 2) the leakage prevention and pressure stability during the circulation of the drilling fluid are accomplished by circulating the drilling fluid with various densities at different depths when running casing; 3) the leakage prevention and pressure stability in the process of running casing are reached by controlling the rate of casing running and the annular back pressure at different stages. The research results provide a basis for pressure control technologies while running casing with negative pressure windows.