ABFEs and obtain mean unsigned error below 1 kcal/mol. We have assessed both equilibrium and non-equilibrium approaches for a large dataset of diverse ligands and proteins. The EQ approach is found to be more accurate and precise than the NEQ approach. We have shown that the claims of the NEQ approach being superior to the EQ one simply based on being computationally less expensive are exaggerated and unjustified. Through a comprehensive evidence-based analysis, it has been established that the EQ approach is preferable over the NEQ approach, particularly for large scale applications. In exactly the same way as for RBFE approaches, there are several implementational aspects that render the NEQ approach more complicated, prone to failure and/or unreliable predictions. A systematic investigation of the various parameters involved in ABFE calculations has been performed and based on that, a set of definitive recommendations have been provided (for both EQ and NEQ approaches) that would allow anyone interested to perform ABFE calculations with reliability. In particular, this analysis for the NEQ approach allows practitioners to better understand and control errors, adjusting the large number of parameters involved in this approach. Furthermore, we have provided evidence that coupling two thermodynamic steps (ligand coupling and removal of restraints in the protein environment) in an ABFE calculation into one can reduce the computational costs by 40% without compromising accuracy and/or precision.