A method for operating an internal combustion engine having an engine with a first number of cylinders and a second number of cylinders and a supercharger arrangement, wherein a charge air flow supplied to the engine is compressed by means of at least one compressor and at least one turbine is acted on by an exhaust gas flow discharged from the engine. In a main operating mode, the engine operates the first number of cylinders in two-stroke operation and the second number of cylinders in four-stroke operation. A scavenging gradient of the engine is greater for the cylinders operated in the two-stroke operation than for the cylinders operated in the four-stroke operation.