The effect of alloying with Mo atoms 4 at.% on the twinning deformation, critical resolved shear stresses (CRSS) for slip τcrsl and twinning τcrtw and plasticity was studied in [1‾11]-, [1‾44]- and [001]- oriented crystals of the Co24Cr24Fe24Ni24Mo4 (at.%) high-entropy alloy (HEA) under tension at 296 and 77 K. The stacking fault energy of the Co24Cr24Fe24Ni24Mo4 HEA, measured in the present paper on the triple dislocation nodes, is equal to 0.027 J/m2. It is shown that initial yield behavior along studied orientations is governed by dislocation slip and the CRSS for slip are independent of crystal orientation. Under tensile strain, twinning develops in the [1‾11]- and [1‾44]- oriented crystals only at 77 K and is not detected in the [001]-oriented crystals. Two types of twins are found in the [1‾11]- and [1‾44]-oriented crystals (thin nanotwins and macrotwins). Nanotwins develop after a low slip deformation of 5–10% and are observed only by transmission electron microscopy. Macrotwins are detected after a significant slip deformation of 20 and 60% and are determined metallographically and X-ray by the precession of the crystal axis, respectively, in the [1‾11]- and [1‾44]-oriented crystals. In the [1‾11]- oriented crystals, there is no precession of the crystal axis due to the development of slip simultaneously in several systems. It is shown that CRSS for nano- and macrotwins are dependent on the crystal orientation. In the [1‾44]-oriented crystals, τcrtw = 212 MPa for nanotwinning and τcrtw = 400 MPa for macrotwinning. In the [1‾11]-oriented crystals, τcrtw = 250 MPa for nanotwinning and τcrtw = 335 MPa for macrotwinning. For the transition to deformation by macrotwinning, it is necessary that the effective stacking fault energy γef is approaching to zero and the condition τcrtw <τcrsl is satisfied. Deformation by macrotwinning suppresses slip multiplicity and shifts the formation of the neck formation according to the Considère condition to higher stress levels. This increases plasticity from 72% at 296 K to 108% at 77 K in [1‾44]-oriented crystals and from 48% at 296 K to 57% at 77 K in [1‾11]-oriented crystals.