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Inland water bodies, which are critical freshwater resources for arid and semi-arid areas, are very sensitive to climate change and human disturbance. In this paper, we derived a time series of major lake surface areas across Xinjiang Uygur Autonomous Region (XUAR), China, based on an eight-day MODIS time series in 500 m resolution from 2000 to 2014. A classification approach based on water index and dynamic threshold selection was first developed to accommodate varied spectral features of water pixels at different temporal steps. The overall classification accuracy for a MODIS-derived water body is 97% compared to a water body derived using Landsat imagery. Then, monthly composites of water bodies were derived for the months of April, July, and September to identify seasonal patterns and inter-annual dynamics of 10 major lakes (>100 km(2)) in XUAR. Our results indicate that the changing trends of surface area of major lakes varied across the region. The surface areas of the Ebinur and Bosten Lakes showed a significant shrinking trend. The Ulungur-Jili Lake remained relatively stable during the entire period. For mountain lakes, the Barkol Lake showed a decreasing trend in April and July, but the Sayram Lake showed a significant expanding trend in September. The four plateau lakes exhibited significant expanding trends in all three seasons except for Arkatag Lake in July. The shrinking of major lakes reflects severe anthropogenic impacts due to agricultural and industrial needs, in addition to the impact of climate change. The pattern of lake changes across the XUAR can provide insight into the impact of climate change and human activities on regional water resources in this arid and semi-arid region.