The mechanical responses of crystallographic orientations [001], [110], and [111] of Al 20.4 Mo 10.5 Nb 22.4 Ta 10.1 Ti 17.8 Zr 18.8 refractory high entropy alloy (RHEA) nanopillars under the uniaxial compression are investigated by the MD simulation using 2NN MEAM potential. The [001]-orientated nanopillar shows the widest elastic deformation regime with the yielding strain about 0.075, compared to the other two nanopillars with the yielding strains about 0.03~0.04. The strength of [111]-oriented nanopillar is the highest, which is about 36.3% and 117% higher than those of [001]- and [110]-oriented nanopillars, respectively. After the strain exceeds the ultimate one, the stress gradually declines with the increasing strain, and then displays small flow stress oscillation during plastic deformation, indicating the stresses saturate at the quasi-steady flow stress. For the [001]-orientated nanopillar, the extent of BCC-HCP phase transition is the most significant at strains below the flow stress regime. From strain 0 to the beginning of the flow stress regime, the local structural transition is the main deformation mechanism, and the dislocation slip becomes the dominant deformation mechanism within the flow stress regime. For the [110]-orientated nanopillar, the dislocation nucleates at the strain between the yielding and ultimate strains, and then the dislocation density increases sharply with the increasing strain until the occurrence of the dislocation slip. The dislocation slip and deformation twinning are two main deformation mechanisms for the [110]-orientated nanopillar. For the [111]-orientated nano-pillar, the dislocation nucleates at the strain larger than the ultimate strain when the stress undergoes an abrupt drop. After the dislocation nucleation, the dislocation density shows a distinct increase during the stress drop, leading to the appearance of dislocation lines. In the flow stress regime, the dislocation density gradually decreases from the maximum value about 600.17 10 19 m -2 to zero with the increasing strain. Local shear strain of [110]-oriented Al20.4Mo10.5Nb22.4Ta10.1Ti17.8Zr18.8 nanopillar during the compression • The mechanical responses of crystallographic orientations [001], [110], and [111] of Al 20.4 Mo 10.5 Nb 22.4 Ta 10.1 Ti 17.8 Zr 18.8 refractory high entropy alloy nanopillars under the uniaxial compression • 2NN MEAM potential parametrization process for the Al-Mo-Nb-Ta-Ti-Zr system using DFT calculation data. • Polyhedral template matching (PTM) method for monitoring the local structural transformation. • Atomic local shear strain for observing dislocation slip band growth • dislocation extraction algorithm (DXA) results for dislocation nucleation and evolution