The Qinghai-Tibet Plateau (QTP) has unique features of high-cold environments and natural conditions, which have limited the natural distribution and orderly development of its population, and then has formed a large and widely distributed Unpopulated Areas (UPAs). However, the information of the area size, distribution extent, geographical characteristics and regional differences of the UPAs in this plateau is still not available. Therefore, it is significant to define accurately the spatial extent and geographical distribution of the UPAs for the assessment of resources and environmental carrying capacity and constructing the national parks and ecological security barrier in this plateau. Based on the distribution information of residential areas in the QTP, from the characteristics of topography, climate, ecology (oxygen content), land use and other elements, the study aims to examine the relationship of natural-ecological-land use system. Therefore, we developed a comprehensive evaluation model of the "UPAs" through the spatial overlay of multiple elements. The key thresholds determined in the aspects of physical and ecological (oxygen content) limits and land use characteristics, were then used to define the geographical distribution and to examine spatial characteristics of the UPAs in the QTP, China. The results showed that: (1) With the cumulative proportion of residential distribution < 0.1%, we defined the topographic thresholds of the UPAs including the elevation > 5665 m, relative height difference > 2402 m, the relief degree of land surface (RDLS) > 8.59, and the climatic thresholds including the relative humidity > 76.2% and the temperature humidity index (THI) < 33 or > 71. (2) According to the distribution of residential areas and oxygen content tolerance of the human being, the oxygen content thresholds of UPAs were determined as air pressure < 500 hPa, oxygen content < 40%. (3) The resultant UPAs on the QTP covers an area of 1912 km 2, including 699 km2 in Xinjiang, 413 km2 in Sichuan, 331 km2 in Tibet, 291 km2 in Qinghai, and 178 km2 in Gansu. The UPAs are scattered sporadically, mostly distributed in Gonggashan Mountain region in Sichuan, the extremely high mountain areas such as Mount Everest in the Himalayas, and the northern Hoh Xil and Lop Nur region, as well as a small part of the UPAs in the Qaidam Basin of Qinghai.