Sodium channels enter the inactivated state from both open (OS) and closed state (CS). It's still unclear how DIVS4 mutations and temperature influence the balance between inactivation from OS and CS. Therefore we performed whole-cell patch-clamp experiments at 5-30°C on HEK293 cells, stably expressing the hNav1.4 a-subunit of WT and a DIVS4 mutation associated with cold induced Paramyotonia Congenita. R1448H mutation did not modify the temperature sensitivity of the channel per se, it slowed open-state inactivation, but accelerated closed-state inactivation in the whole temperature range. Further cooling uncovered a striking difference between WT and R1448H. For WT, the alignment of the time constants associated with fast inactivation is represented by a bell shaped curve with a maximum around ?80 mV. The analogous alignment for R1448H is a curve with two maxima. We propose that accelerated closed-state inactivation influences the time constants of fast inactivation in the range of - 60 to -40 mV. Channels which deactivate in this voltage range have a higher probability to go to the closed-inactivated state than back to the OS. This would explain the accelerated current decay in this voltage range.