A failure determination system and method for an internal combustion engine and an engine control unit are provided which are capable of properly determining a failure of a variable valve mechanism for inactivating a valve system associated with at least one of cylinders during a predetermined operation of the engine, by discriminating a misfire caused by the failure of the mechanism from a normal misfire. Fuel injection valves inject fuel for each cylinder and oxygen concentration of exhaust gases is detected. A misfire condition is detected on a cylinder-by-cylinder basis. Fuel injection to a misfiring cylinder is stopped. A failure of the mechanism is determined, when a parameter based on the oxygen concentration detection indicates a richer value of an actual air-fuel ratio of the exhaust gases than a predetermined reference value does, under a condition of the fuel injection being stopped.