In this study, we demonstrate that absolute binding free energy calculations can successfully estimate affinity changes in the fragment optimisation process. Whilst not always being able to clearly support elaboration decisions, the right direction in the affinity change was captured for the vast majority of cases (46 of the 52 ligand pairs involved in the 22 elaboration decisions). Despite occasional challenges in accurately matching experimentally derived binding free energies, the predictive power displayed here shows that ABFEs can be suitably used to not only act to orthogonally validate fragment hits but also to guide fragment optimisation.