Hybrid desiccant wheel systems are widely adopted for low humidity control in industrial field. The clarification of process and regeneration air management is required to achieve energy saving. The all-fresh air dehumidification and primary return air dehumidification are compared for a high-polymer desiccant wheel and heat pump system. The system simulation model was established and validated by field test results of a low humidity industrial workshop. Firstly, the fresh air flowrate and air stream pattern are analyzed and optimized, for achieving low annual energy consumption. Secondly, the system power of the optimized fresh air mode and primary return air mode were compared for different outdoor air temperature, outdoor air humidity and indoor humidity requirement. At last, energy saving rate of all fresh air dehumidification mode was analyzed for five typical climate zones in China. It was found that the optimized fresh air flowrate numerically equals to the summation of regeneration air flowrate and the positive pressure required air flowrate. With the optimized fresh air flowrate, 20.4% of the annual energy can be saved compared with primary return air system. Outdoor air conditions were divided into three zones on psychrometric chart, and the boundaries are related to indoor temperature and humidity ratio. Fresh air is energy efficient for high temperature high humidity and low temperature low humidity conditions. By using fresh air dehumidification mode, the energy saving rate can reach 69.6% for severe cold region. Primary return air dehumidification mode is suitable for HSCW and HSWW region for indoor relative humidity of 40%, and 41.8% of the energy can be saved.