Since the antiquity the area of Kalithea (Καλλιθέα) was known for its thermal, therapeutic springs. In 1927, under the administration of Mario Lago, a systematic study of the waters was initiated headed by Gustavo Gasperini, his son Carlo and Enea Brunetti (who later became the of the director of Terme di Calitea). The study concluded that the water had a range of important properties and proposed the development of the area with the creation of a Thermal Spa Institution that would function in accordance to the stringiest health requirements of the time.
In late December 1928 the Government of the Islands of the Aegean decided the construction of the building complex. The project was commissioned to the famous architect Pietro Lombardi. His plans for Kalithea Thermal Spa were considered among the best architectural compositions of the time, masterfully combining different architectural styles from Arabic to Baroque. It was considered, world-wide, as one of the most emblematic architectural constructions of the 1930s.