A general method for fault detection and isolation is proposed and applied to inverter faults in drives of electric vehicles. This method is based on a change-detection algorithm, which allows multiple fault indices to be combined for retrieving the most likely state of the drive. The drive topology under study is a six-leg inverter associated with a three-phase open-end winding machine. Due to the inherent fault-tolerant topology, the conventional fault indices are no longer effective. Therefore, an analysis of simulations in faulty conditions leads to the derivation of suitable fault indices. These are based on the envelope of the phase currents as well as their instantaneous frequency. Specific operating conditions related to the electric vehicle environment are taken into account, such as the flux-weakening region and energy recovery. In these modes of operation, fault detection and isolation can be affected by uncontrolled currents circulating through the free-wheeling diodes. Finally, the performances of the fault detection and isolation scheme are evaluated under steady state and non-stationary conditions through simulations and experimental results.