The rapid delayed rectifier, IKr, is believed to have h-erg (human ether-à-go-go related gene) as its molecular basis. A recent study has shown that rectification of h-erg involves a rapid inactivation process that involves rapid closure of the external mouth of the pore or C-type inactivation. We measured the instantaneous current to voltage relationship for h-erg channels using the saponin permeabilized variation of the cut-open oocyte clamp technique. In contrast to C-type inactivation in other voltage-gated K+ channels, the rate of inactivation was strongly voltage dependent at depolarized potentials. This voltage dependence could be modulated independently of activation by increasing [K+]0 from 2 to 98 mM. These results suggest that inactivation of h-erg has its own intrinsic voltage sensor.