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Many devastating earthquakes inflicted heavy casualties and property losses in the seismically active China Seismic Experimental Site area (CSES: 97.5° ~ 105.5°E, 21° ~ 32°N). We performed a first-order seismic zoning based on Neo-deterministic Seismic Hazard Assessment (NDSHA) in the study area delimited by 94° ~ 108°E and 19° ~ 35°N, containing the South-East margin of the Tibetan Plateau and the Sichuan-Yunnan region. The seismic hazard is expressed by maps of peak ground displacement (PGD), peak ground velocity (PGV) and design ground acceleration (DGA) values, extracted from synthetic seismograms computed at a regional scale and mapped on a regular grid of 0.2° × 0.2° over the study area. For the computation of synthetic seismograms, we considered and updated all the available geophysical-geological-tectonic information, including historical and instrumental earthquake catalogues, seismogenic zones, seismogenic nodes, focal mechanisms, and geophysical structural models. We tested the performance of our assessments with available data (i.e., after the Great Wenchuan (2008, May 12th, Ms = 8.0) and Lushan (2013, April 20th, Ms = 7.0) earthquakes) and verified the negligible influence of large events located “far” from the study area. The results indicate the high seismic hazard of the region, with a particular attention (i.e., where DGA > 0.6 g) to the areas located around the main fault zones, e.g., the Longmenshan, Anninghe and Zemuhe Fault Zones. These first-order NDSHA zoning findings may serve as a knowledge basis to support both large- to mid-range preparedness actions and (multi-scenario) site-specific studies.