We assessed the performance of the newly fitted Parsley forcefield in binding free energy calculations based on molecular dynamics simulations following suggested best practices for benchmarking binding affinities. The test set consisted of 8 protein targets with a total of 199 ligands (Supporting Information, Table ), using a set commonly referred to as the "JACS dataset" from a prior study published in that journal and frequently used by the community. For a fair comparison to previously published results, the initial ligand and protein structures were obtained from prior benchmark work. These structures are available in the protein-ligand-benchmark repository. Relative binding free energies were calculated employing alchemical perturbations between pairs of ligands in water and the protein complex. These calculations employed a non-equilibrium workflow based on GROMACS and pmx. For the ligand molecules, the Parsley forcefield was used as parameters. The protein was parameterized with the AMBER ff99sb*ILDN force field and a TIP3P explicit water model was employed. We chose AMBER ff99sb*ILDN as the protein force field because we expect Parsley to have the best compatibility with the AMBER family of force fields, as its nonbonded parameters are ultimately taken from Parm@Frosst, an AMBER-compatible small molecule force field. The water model was chosen as TIP3P due to the widespread use of this water model with the AM-BER family of protein force fields. To mimic physiological conditions, ions (150 mM NaCl) and additional counterions to neutralize the system were added to the dodecahedral simulation boxes.