Alchemical free-energy calculations are now widely used to drive or maintain potency in small-molecule lead optimization with a roughly 1 kcal/mol accuracy. Despite this, the potential to use free-energy calculations to drive optimization of compound selectivity among two similar targets has been relatively unexplored in published studies. In the most optimistic scenario, the similarity of binding sites might lead to a fortuitous cancellation of errors and allow selectivity to be predicted more accurately than affinity. Here, we assess the accuracy with which selectivity can be predicted in the context of small-molecule kinase inhibitors, considering the very similar binding sites of human kinases CDK2 and CDK9 as well as another series of ligands attempting to achieve selectivity between the more distantly related kinases CDK2 and ERK2. Using a Bayesian analysis approach, we separate systematic from statistical errors and quantify the correlation in systematic errors between selectivity targets. We find that, in the CDK2/CDK9 case, a high correlation in systematic errors suggests that free-energy calculations can have significant impact in aiding chemists in achieving selectivity, while in more distantly related kinases (CDK2/ERK2), the correlation in systematic error suggests that fortuitous cancellation may even occur between systems that are not as closely related. In both cases, the correlation in systematic error suggests that longer simulations are beneficial to properly balance statistical error with systematic error to take full advantage of the increase in apparent free-energy calculation accuracy in selectivity prediction.