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Background: Hand foot and mouth disease (HFMD) is becoming one of the common human infectious diseases in China. Previous studies have described HFMD in tropical or coastal areas of Asia-Pacific countries. However, limited studies have thoroughly studied the epidemiology and potential risk factors for HFMD in inland areas with complex environmental conditions. Methodology/Principal findings: Using the data from 2009 to 2018 on reported cases of Xinjiang Uighur Autonomous Region, we characterized the epidemic features of HFMD. Panel negative binomial model was used to identify climate, geographical and demographic determinants for HFMD incidence. A total of 70856 HFMD cases (average annual incidence: 305 per million persons) were reported in Xinjiang during the 10-year study period, of which 10393 (14.7%) were laboratory-confirmed and 98 (0.1%) were severe. HFMD peaked in summer every year during the study period, and incidence in 2012, 2015, 2016 and 2018 had minor peaks in autumn. After adjusting the school or holiday month, multiple factors were found to affect HFMD epidemiology: urban area being major land cover type (incidence risk ratio, IRR 2.08; 95% CI 1.50, 2.89), higher gross domestic product per capita (IRR 1.14; 95% CI 1.11, 1.16), rise in monthly average temperature (IRR 1.65; 95% CI 1.61, 1.69) and monthly accumulative precipitation (IRR 1.20; 95% CI 1.16, 1.24) predicted increase in the incidence of HFMD; farmland being major land cover type (IRR 0.72; 95% CI 0.64, 0.81), an increase of percentage of the minority (IRR 0.91; 95% CI 0.89, 0.93) and population density (IRR 0.98; 95% CI 0.98, 0.99) were related to a decrease in the incidence of HFMD. Conclusions/Significance: In conclusion, the epidemic status of HFMD in Xinjiang is characterized by low morbidity and fatality. Multiple factors have significant influences on the occurrence and transmission of HFMD in Xinjiang. Author summary: Hand foot and mouth disease (HFMD) is one of the common human infectious disease threating Asia-Pacific countries. To explore the epidemiology and environmental risk factors for HFMD in inland China, we utilized 10-year HFMD surveillance data in Xinjiang Uighur Autonomous Region and combined multiple spatial-temporal statistical analyses. We identified spatial-temporal clusters of HFMD incidence and found that multiple factors could affect HFMD incidence: urban area being major land cover type, higher gross domestic product per capita, rise in monthly average temperature and monthly accumulative precipitation predicted increase in the incidence of HFMD; farmland being major land cover type, an increase of percentage of the minority and population density were related to a decrease in the incidence of HFMD. Our findings facilitate the understanding of HFMD epidemiology and risk factors in different geographic regions, which are crucial for conducting prevention and control strategies of HFMD. [ABSTRACT FROM AUTHOR]