<p>CoCrWNi alloy is a suitable biomaterial for cardiac stent applications due to its biocompatibility, corrosion resistance, and wear resistance. However, conventional alloy designs by trial and error can be time-consuming and expensive. Hence, computational methods can control the stacking fault energy (SFE), which affects the mechanical properties, and develop a new CoCrWNi alloy with much lower time and cost. However, calculating the SFE requires a thorough investigation of theoretical and experimental methods due to the complicated effect between different atoms in the complex alloy system. In this study, we investigated the effect of Cu, Mn, and Fe addition on the SFE of CoCrWNi alloy using simulations (first principle and computational thermodynamics) and compared it with the experiment for the first time. The addition of Cu, Mn, and Fe to the CoCrWNi alloy increases the SFE, as demonstrated by both thermodynamic and first-principles calculation methods. The intensity of the hcp phase decreased with increasing Cu content in the CoCrWNi alloy, proving the simulation result that the SFE will increase. Furthermore, the peak analysis of X-ray diffraction using the peak shift and peak broadening method shows that the increase of Cu concentrations will reduce the deformation fault probability, twin fault probability, and stacking fault probability and then increase the SFE. Combining Cu and Mn alloying elements with the CoCrWNi alloy can be used to design a new CoCrWNi alloy that can increase the SFE to the desired value. In the present work, investigating the electronic structure, such as interlayer distance, charge density difference, and density of states, can explain the increasing SFE. This study can be helpful as a guideline for designing new CoCrWNi alloys with superior mechanical properties.</p> Graphical Abstract <p></p>