Excited by ocean currents, random wave and vessel motion, deepwater drilling risers exhibit significant dynamic response. In time domain, a method is proposed to calculate the nonlinear dynamic response of deepwater drilling risers subjected to random wave and dynamic large displacement vessel motion boundary condition. Structural and functional loads, external and internal pressure, free surface effect of irregular wave, hydrodynamic forces induced by current and wave, as well as wave and low frequency (drift) motion of the drilling vessel are all accounted for. An example is presented which illustrates the application of the proposed method. The study shows that long term drift motion of the vessel has profound effect on the envelopes of bending stress and lateral displacement, as well as the range of lower flex joint angle of the deepwater riser. It can also be concluded that vessel motion is the principal dynamic loading of nonlinear dynamic response for the deepwater risers rather than wave force.