The function of voltage-gated human ether-à-go-go related gene (hERG) K(+) channels is critical for both normal cardiac repolarization and suppression of arrhythmias initiated by premature excitation. These important functions are facilitated by their unusual kinetics that combine relatively slow activation and deactivation with rapid and voltage-dependent inactivation and recovery from inactivation. The thermodynamics of these unusual features were examined by exploring the effect of temperature on the activation and inactivation processes of hERG channels expressed in Chinese hamster ovary cells. Increased temperature shifted the voltage dependence of activation in the hyperpolarizing direction but that of inactivation in the depolarizing direction. This increases the relative occupancy of the open state and contributes to the marked temperature sensitivity of hERG current magnitude observed during action potential voltage clamps. The rates of activation and deactivation also increase with higher temperatures, but less markedly than do the rates of inactivation and recovery from inactivation. Our results also emphasize that one cannot extrapolate results obtained at room temperature to 37 degrees C by using a single temperature scale factor.