Here, building on our prior efforts to make ABFE calculations routine and efficient , we evaluate the effectiveness of ABFE calculations as a tool to refine virtual screening calculations. Thus, we docked ∼70,000 active and decoy compounds across 3 protein targets, obtaining good initial enrichment of actives among the top-scored compounds. We then ran ABFE calculation on sets of high-scoring compounds for each target and found that the ABFE results differentiate true actives from decoys better than do the docking results. The present paper details the methods used and the results obtained and discusses potential implications and sources of error.