The Simcyp Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within 2-fold of observed values for 73% of the drugs (oral route) and 78% of the drugs (intravenous route) when microsomal binding was disregarded, and for 93% (oral) and 100% (intravenous) when it was considered. Irrespective of whether microsomal binding was considered, the predicted fold variability fell within 2-fold of the observed variability for 80% (oral) and 67% (intravenous) of the drugs.