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The Shaksgam Valley, located on the north side of the Karakoram Mountains of western China, is situated in the transition zone between the Indian monsoon system and dry arid climate zones. Previous studies have reported abnormal behaviors of the glaciers in this region compared to the global trend of glacier retreat, so the region is of special interest for glacier-climatological studies. For this purpose, long-term monitoring of glaciers in this region is necessary to obtain a better understanding of the relationships between glacier changes and local climate variations. However, accurate historical and up-to-date glacier inventory data for the region are currently unavailable. For this reason, this study conducted glacier inventories for the years 1970, 1980, 1990, 2000 and 2014 (i.e., a ~10-year interval) using multi-temporal remote sensing imagery. The remote sensing data used included Corona KH-4A/B (1965–1971), Hexagon KH-9 (1980), Landsat Thematic Mapper (TM) (1990/1993), Landsat Enhanced Thematic Mapper Plus (ETM+) (2000/2001), and Landsat Operational Land Imager (OLI) and Thermal Infrared Sensor (TIRS) (2014/2015) multispectral satellite images, as well as digital elevation models (DEMs) from the Shuttle Radar Topography Mission (SRTM), DEMs generated from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) images (2005–2014), and Advanced Land Observing Satellite (ALOS) World 3D 30 m mesh (AW3D30). In the year 2014, a total of 173 glaciers (including 121 debris-free glaciers) (>0.5 km2), covering an area of 1478 ± 34 km2 (area of debris-free glaciers: 295 ± 7 km2) were mapped. The multi-temporal glacier inventory results indicated that total glacier area change between 1970–2014 was not significant. However, individual glacier changes showed significant variability. Comparisons of the changes in glacier terminus position indicated that 55 (32 debris-covered) glaciers experienced significant advances (~40–1400 m) between 1970–2014, and 74 (32 debris-covered) glaciers experienced significant advances (~40–1400 m) during the most recent period (2000–2014). Notably, small glaciers showed higher sensitivity to climate changes, and the glaciers located in the western part of the study site were exhibiting glacier area expansion compared to other parts of the Shaksgam Valley. Finally, regression analyses indicated that topographic parameters were not the main driver of glacier changes. On the contrary, local climate variability could explain the complex behavior of glaciers in this region.