As the result of increasingly strict emission regulations and demand of fuel reduction, current light and medium duty engines are being highly boosted with complex two-stage turbocharging systems. The purpose of this work is to investigate the influence of two-stage turbocharging system parameters on the engine performance and the optimization of these parameters. An analytical pre-design model of the series two-stage turbocharging system for an internal combustion engine was developed, which builds the relationship between total pressure ratio, total expansion ratio and other two-stage turbocharging system parameters. Considering total expansion ratio as a function of expansion ratio between HP and LP turbine, minimum total expansion ratio can be determined using this model. The ratio of total pressure ratio to total expansion ratio, engine brake thermal efficiency and total heat exchange of coolers are considered as the parameters for engine performance evaluation. Influence of two-stage turbocharging system parameters, such as efficiency of compressors and turbines, cooling water temperature, cooler efficiency, pressure loss of coolers, EGR rate and bypass gas rate of wastegate, etc., on engine performance was analyzed respectively. Results show that the performance of a two-stage turbocharging engine is impacted mainly by LP turbocharger efficiency, intercooler performance and air filter performance.