Larissa, the capital of Thessaly, is located in the eastern part of Central Greece, at the southern border of a Late Quarternary graben, the Tyrnavos Basin. Palaeoseismological, morphotectonic, and geophysical investigations as well as historical and instrumental records show evidences for seismic activity in this area. Previous investigations documented the occurrence of several moderate to strong earthquakes during Holocene time on active faults with recurrence intervals of a few thousand years. The historical and instrumental records suggest a period of seismic quiescence during the last 400 to 500 years. The present archaeoseismological research, based on a multidisciplinary approach is devoted to improve the knowledge on past earthquakes, which occurred in the area. This study focuses on damages observed on the walls of the scene building of the Great Theatre of Larissa. The Theatre was built at the beginning of the 3rd century BC and consists of a semicircular auditorium, an almost circular arena and a main scene building. Archaeological and historical investigations document a partial destruction of the theatre during the 2nd-1st century BC. Recent excavations show that the building complex after it was repaired suffered additional structural damages, probably from seismic loading. The damages investigated in detail are displacements, rotations and ruptures of numerous blocks at the walls of the scene building. In order to test the earthquake hypothesis as cause of the damages a simplified seismotectonic model of the Tyrnavos Basin and its surroundings was used with a composite earthquake source model to calculate synthetic seismograms at the Larissa site for various earthquake scenarios. Horizontal to vertical seismic ratio (HVSR) measurements in the theatre and its vicinity were used to estimate local site effects. The synthetic seismograms are then used as input accelerations for a finite element model of the walls, which simulates seismically induced in-plane sliding within the walls. Results show that some of the surrounding faults have the potential to produce seismic ground motion that can induce in-plane sliding of blocks. Model calculations were used to constrain the characteristics of the ground acceleration and infer the causative fault and earthquake by comparing the calculated and observed distribution of the displacements of the blocks. Ground motions with a PGA at the site of 0.62-0.82 g, which could be induced by an M 5.8-6.0 earthquake on the nearby Larissa Fault, would be sufficient to explain the damage