Although lower uncertainties of the estimated ∆G are desired, the long alchemical transition times quickly become intractable for large scale ligand binding affinity scans. Therefore, it is necessary to balance the trade-off between the available simulation time and the attainable precision. This, naturally, requires a robust uncertainty estimation for the ∆G estimates. It has been observed that relying on the statistical uncertainties from the ∆G estimators, either analytical expressions, or bootstrapped values, may not be reliable. Therefore, in this work we rely on independent repeats of the whole free energy calculation procedure to gain access to the variation of the ∆G estimates. Subsequently, we incorpo-rate both, uncertainties from the independent replicas and statistical uncertainty from the estimator by means of bootstrap into a single uncertainty value.