The withdrawal characteristics of barbital and pentobarbital after chronically equivalent treatment suggested that the longer acting barbital was less liable to produce physical dependence. To distinguish this potential pharmacodynamic difference from the known pharmacokinetic differences between the 2 drugs, the rate of elimination of each was adjusted to mimic that of the other. The rate of barbiturate elimination after chronically equivalent pentobarbital dosing was reduced by barbital substitution or by 1st-order pentobarbital dose reduction, with the result that withdrawal signs became mild and appeared later (3 days postdrug). The rate of barbiturate elimination after chronically equivalent barbital dosing was increased by pentobarbital substitution or by peritoneal dialysis of barbital, with the result that withdrawal signs became severe and appeared sooner (within 1 day). The key role of the rate of barbiturate elimination to expose underlying physical dependence to barbiturates was supported. Physical dependence and its expression in withdrawal must be regarded separately to evaluate and compare critically the dependence capability of different drugs.