To operate an internal combustion engine of a motor vehicle, during a plurality of driving cycles of the motor vehicle at least one operating variable is recorded during each run which is representative of a harmful substance content of an exhaust gas of the internal combustion engine. The recorded runs are analyzed with respect to recurring run patterns. In a current driving cycle of the motor vehicle, a target value of an ammonia charge level of an exhaust gas catalyst of the internal combustion engine is determined using the recurring run pattern, depending on which, at least one actuating signal for an actuator is determined, the position of which affects an actual ammonia charge level of the exhaust gas catalyst. In order to convert the determined target value of the ammonia charge level of the exhaust gas catalyst, the actuator is controlled as a function of the actuating signal.