Heat pump desiccant wheel hybrid systems can control indoor temperature and humidity for industrial and civil buildings. To clarify the boundary of heat pump combined single-stage desiccant wheel system and two-stage desiccant wheel system for judging the optimal system under different conditions, the performance of the two systems is analyzed with experiment and simulation method. Firstly, the fresh air process is compared for different humidity set points under typical operation conditions. Secondly, the energy moisture ratio (EMR) of desiccant wheels is analyzed. At last, based on system energy consumption and economy, the humidity boundary of the single-stage and the two-stage dehumidification system is proposed, under different conditions. It is found that the energy performance of desiccant wheel increases with the reducing of humidity set point for both systems, and higher EMR can be obtained by the desiccant wheel of the single-stage dehumidification system for all operation modes. The two-stage dehumidification system is more energy efficient when humidity for the controlled space is lower than 49%, 55% and 40% for high temperature mode, typical summer mode and typical dehumidification mode, separately. With the proposed operation boundary, the optimal system can be quickly judged according to the humidity control requirement and outdoor environment.