Abstract Desiccant dehumidification is an alternative solution for independently processing air humidity, which can simultaneously accommodate the sensible and latent heat loads even in high-humidity areas (e.g., Hong Kong). However, there is still a lack of comparative investigation in practical applications between the traditional condensation dehumidification and desiccant dehumidification, which is of great significance for revealing the effectiveness of desiccant dehumidifiers. Therefore, this study conducted on-site measurements in four different types of buildings. Moreover, the annual performance of different dehumidification solutions based on the set values of real buildings were simulated to further compare the dehumidification capacity, energy consumption, and cost performance. Results showed that the indoor humidity control of the measured buildings was substandard when using condensation dehumidification, and it was significantly improved after installing desiccant dehumidifiers. Compared with overcooling & reheating condensation dehumidification that achieved a similar humidity level, the annual energy savings of the desiccant dehumidification were respectively up to 4.9% and 7.7% for an office and a hotel based on the simulation results. The economic analysis indicated that desiccant dehumidification was more cost-effective than condensation dehumidification with overcooling & reheating. Finally, comprehensive evaluations were presented to facilitate the selection of dehumidification solutions.