Meeting thermal comfort in buildings with high latent loads requires the treatment of the air humidity with specific technologies. Desiccant based systems have proved to be effective in removing ventilation latent load in heating-ventilation and air conditioning systems. Typically, desiccant based systems are part of the air-handling units, which control both temperature and humidity. Based on the above, this paper presents an innovative solution designed to be integrated in the building envelope. It consists of a honeycomb desiccant block placed inside a ventilated façade. The regeneration of the desiccant material is carried out by a solar air collector, which is also integrated in the façade. The aim of the system is to dehumidify the ventilation air before entering the air-handling unit using the façade as an active element of the system. The solution is built at a pilot scale and tested under Mediterranean climate conditions. The experimental tests lead to a numerical model implemented in TRNSYS. This model is used to evaluate the performance of the solution in an office building comparing with a conventional cooling coil system, the conventional alternative. Results show that, under Mediterranean climate, the desiccant façade ensures a humidity comfort greater than 92% in neutral supply air conditions (26 °C and 50%). Under the same neutral conditions, conventional systems can only achieve this level of comfort by supplying colder air in order to force the condensation of the air in the cooling coil, which entails an energy consumption increase of 29%. Last, results confirm that the desiccant façade leads to lower energy consumption in both Mediterranean and Subtropical climates while conventional systems are more appropriate in cold semi-arid climates.