The molecular dynamics simulation is applied to investigate the liquid flow in rough nanochannels with a focus on interfacial velocity slip via three-dimensional Couette flow system. The typical liquid spatial distribution, velocity profile and slip length for liquid flow in rough nanochannels are evaluated and compared with smooth nanochannel. The effects of liquid-solid interaction, surface roughness and shear flow orientation on slip behavior of liquid flow in rough nanochannels are all investigated and discussed. The results indicate that, regardless of whether the liquid flow in transverse or longitudinal flow configuration, the rough surface induces extra energy losses and contributes to the reduction of interfacial velocity in nanochannel when compared with smooth surface. A larger roughness size introduces a more irregular near-wall flow, which results in a smaller interfacial velocity slip. In addition, irrespective of surface condition, increases in liquid-solid interaction strength lead to small interfacial velocity slip and expand the extent of velocity nonlinearity in wall-neighboring region. In particular, the slip behavior of liquid flow in rough nanochannels is also influenced by the shear flow orientation. Interestingly, we find that interfacial velocity slip at the rough solid surface in transverse flow configuration is smaller than that in longitudinal flow configuration. (C) 2014 Elsevier B.V. All rights reserved.