Compared with spaces air-conditioned for thermal comfort, cleanrooms often have special requirements on dry bulb temperature, relative humidity and particle concentrations. It is a challenging task to achieve those requirements with minimum energy consumption, especially when different parameters interfere with each other. A significant amount of energy would be wasted if the system is not properly designed and controlled. This paper firstly provides an overview and a discussion on the essentials for design and control of cleanroom air-conditioning systems. The existing systems and controls are categorized into three typical options and their performances are then analyzed based on different weather and load conditions. For new design, the "fully decoupled option" is the preferred option for humid sub-tropical regions. The analysis results are applied in a retrofit project for a pharmaceutical factory located in Hong Kong, a humid sub-tropical city, which employed the "interactive option". This system is proposed to operate as a "partially decoupled option" in this project since such retrofit requires no modification on the existing hardware. The retrofitted system option has been on-site tested in mild weather condition, which provided 69.6% and 87.8% reductions of cooling and heating consumptions respectively. More comprehensive comparison tests are also conducted on a dynamic platform built on Matlab/Simulink. (C) 2017 Elsevier Ltd. All rights reserved.