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Background: Human African trypanosomiasis (HAT), also known as sleeping sickness, persists as a public health problem in several sub-Saharan countries. Evidence-based, spatially explicit estimates of population at risk are needed to inform planning and implementation of field interventions, monitor disease trends, raise awareness and support advocacy. Comprehensive, geo-referenced epidemiological records from HAT-affected countries were combined with human population layers to map five categories of risk, ranging from "very high" to "very low," and to estimate the corresponding at-risk population. Results: Approximately 70 million people distributed over a surface of 1.55 million km2 are estimated to be at different levels of risk of contracting HAT. Trypanosoma brucei gambiense accounts for 82.2% of the population at risk, the remaining 17.8% being at risk of infection from T. b. rhodesiense. Twenty-one million people live in areas classified as moderate to very high risk, where more than 1 HAT case per 10,000 inhabitants per annum is reported. Discussion: Updated estimates of the population at risk of sleeping sickness were made, based on quantitative information on the reported cases and the geographic distribution of human population. Due to substantial methodological differences, it is not possible to make direct comparisons with previous figures for at-risk population. By contrast, it will be possible to explore trends in the future. The presented maps of different HAT risk levels will help to develop site-specific strategies for control and surveillance, and to monitor progress achieved by ongoing efforts aimed at the elimination of sleeping sickness. Author Summary: The present thrust towards the elimination of human African trypanosomiasis (HAT, or sleeping sickness) requires accurate information on how many people are at risk of contracting the disease, and where they live. This information is crucial to target field interventions effectively and efficiently, as well as to monitor progress towards the elimination goal. In this paper, a Geographic Information System was used to delineate areas at different levels of risk. To this end, accurate data on the spatial distribution of HAT cases (period 2000–2009) were collated and combined with maps of human population. A total of 70 million people are estimated to be at risk of contracting sleeping sickness in Africa. This population is distributed over a surface of one and a half million square kilometres, an area six times that of the United Kingdom. Half of the people and of the areas at risk are found in the Democratic Republic of the Congo. [ABSTRACT FROM AUTHOR]