Human and rat hepatocytes have a strong tendency to underpredict hepatic intrinsic clearance (CLint) and the extent of underprediction increases with increasing observed CLint. In this study, application of the log average rat hepatocyte-rat in vivo empirical scaling factor (ESF) of 4.2 to human hepatocyte prediction successfully removed bias but did not improve precision. An analogous method using individual drug rat ESFs only achieved marginal improvement in accuracy but not precision. A novel approach to resolve clearancedependent prediction, involving rat ESFs calculated for particular (order of magnitude) ranges of observed CLint (log average range, 0.1222.1) improved human prediction precision but only modestly reduced bias. However, rat in vivo CLint was several-fold greater than human in vivo CLint and this was reflected in greater rat hepatocyte and microsome CLint, suggesting that rat metabolic enzymes are more efficient than their human counterparts, by several-fold. By applying the segregated rat ESFs followed by the human/rat CLint ratio, which was consistent regardless of CLint (log average 3.5), both accuracy and precision were improved, providing both a means of mitigating clearance dependence and reaffirming the potential role of rat hepatocytes for prediction of human metabolic CLint. These cross-species observations indicate that underprediction from human in vitro systems may be predominantly consequential of an intrinsic property of the in vitro system rather than individual drug properties.