It is well known that the CoCrFeMnNi equiatomic high-entropy alloy (HEA) exhibits excellent irradiation resistance. It is very difficult to form vacancy clusters in this alloy. In the present study, vacancy cluster formation was investigated for three (CoCrNi) and four element medium-entropy alloys (MEAs) in a CoCrFeNi system with the same crystal structure as that of a CoCrFeMnNi HEA. Stacking fault tetrahedra (SFTs), which are a type of vacancy cluster, were observed clearly in both MEAs, which were deformed at high speed, after annealing at 373 K. For comparison, Ni and 316 L stainless steel (SS316L) were also subjected to high-speed deformation experiments. SFTs with high density were clearly observed in the Ni sample after annealing at 773 K, but these were not observed in the SS316L sample. The SFT density was significantly lower in MEAs than that in pure Ni. This result indicates that the CoCrNi and CoCrFeNi MEAs also exhibit good irradiation resistance similar to that of SS316L. Further, calculation results based on the first principles indicate that the binding energies of di-, tri-, and tetra-vacancy clusters in the CoCrNi and CoCrFeNi MEAs, are positive. However, the attractive energy of the tri-vacancy cluster in the CoCrFeMnNi HEA is negative. Display omitted ●High density SFTs were clearly observed in Ni after high-speed deformation, but these were not observed in the SS316L.●SFTs were also observed in the MEAs after high-speed deformation, but their density was significantly low.●Simulation results indicate that the binding energies of di-, tri-, and tetra-vacancy clusters in the MEAs are positive.●Vacancy clusters were formed by ion irradiation at 300 K, and some were stable even annealing at 773 K.●The attractive energy of the tri-vacancy cluster in the CoCrFeMnNi HEA is negative.