Aims: Our study is aimed at determining the risk factors of Human African Trypanosomiasis (HAT) in Mbuji Mayi, Eastern Kasai Province, Democratic Republic of the Congo. Study Design: We used a case-control design with a ratio of 2 controls for every HAT case. Place and Duration of Study: Our multidisciplinary research team collected primary data on cases of HAT patients treated at the Referral and Treatment Center of Dipumba in Mbuji Mayi in 2012 and on their controls of similar gender and age, living in Mbuji Mayi, but free of HAT infection. Methodology: We analyzed data, using both descriptive and analytical statistical procedures such univariate and multivariate methods of logistic regression. The association between the different factors studied and HAT infection has been determined by estimating the odds-ratio (OR) with a confidence interval (CI) of 95% and a P-value of less than 0.05. We interviewed 180 subjects (60 cases and 120 controls). Results: The 60 cases were predominantly male (male-female ratio of 2.2:1) with the majority (53%) in the age group of 20-40 years. Subjects in the age group of over 40 represented 28.3% of the patients. The same patterns were seen in the control group. The age of interviewees varies from 11 to 65 years. HAT cases reported drawing water from wells (16.7% vs 6.7%; P > .05), walking along the river bed and in the peat lands (11.7% vs 9.2%; P > .05) at a higher rate than controls. The HAT cases reported involvement in various activities that put them in much closer proximity with water sources: bathing (8.3% vs 6.6%; P >.05), dishwashing and laundry (20% vs 37.5%), fetching household water (50% vs 24.2%; P<.0001), cassava retting roots (1,7% vs 7.5%), diamond digging in the mines (51.7% vs 21.6%; P < .0001), trafficking or buying diamond from diggers (13,3% vs 8.3% ; P > .05). Conclusion: Involvement in activities that connect with water sources increases the risk of acquiring HAT infection in Mbuji Mayi.