This paper uses a R&D complex as a case study to examine and illustrate how a hybrid approach can be used to provide an optimal HVAC solution for massive R&D complexes to meet energy and comfort requirements. The R&D complex consists of 25 floors including 4 subterranean floors with a total usable space of 300,000 m2. According to the load characteristics, the complex is divided into two areas: exterior zones and interior zones. The exterior zones are exposed to the outdoor weather conditions, thus their heating and cooling loads fluctuate more throughout the day. To deal with these changing loads, a total of 273 variable refrigerant flow (VRF) systems with 3142 indoor units of various types are used. These systems are equipped with high efficiency inverter driven scroll compressors. The interior zones have a relatively stable heating and cooling loads, are hence served by 4 absorption chillers and 3 three centrifugal chillers. This paper will begin with an architecture overview and objectives of HVAC systems design, followed by in-depth analysis and comparisons of different HVAC system design options in terms of energy efficiency, human comfort, initial investment and system life cycle costs. Extensive CFD studies were conducted to investigate the impact of different types of indoor units on indoor temperature and air flow distribution. Finally, we will present an optimal operation algorithm and demonstrate its energy saving potential with field test data.