ABSTRACT World Health Organization (WHO) earmarked Human African Trypanosomiasis for elimination from Nigeria in 2015, making it one of the Country’s (Nigeria) priority diseases listed for surveillance through integrated disease surveillance and response. HAT is a major public health problem in sub-Saharan Africa, where it affects mainly the rural poor and is usually fatal when untreated. The objective of the study was to assess the prevalence of HAT and the level of knowledge exhibited by the people about the disease, its risk factors among the residents of Delta State, Nigeria. A cross sectional study was conducted in Delta State Nigeria from September to December 2011. Structured questionnaires were used to collect data on demographics, knowledge and attitude about HAT and also exposure to risk. Study population was 1,028 residents, aged five years and above, from seven Local Government Areas (LGAs) in the State. Blood samples of respondents were collected for HAT screening using the card agglutination Test for Trypanosoma brucei gambiense (CATT/T.b. gambiense) reagents and kits. Lymph node aspirates and cerebrospinal fluid of CATT positive respondents were examined for the parasite. Out of the 672 respondents about the knowledge of HAT, 579 (86.2%) knew at least one correct symptom, 578 (86.0%) knew the cause and mode of transmission of HAT, 562 (83.6%) knew how to seek care while 612 (90.7%) knew how to protect themselves from the vector. 142 (21.1%) with knowledge about HAT got the information from several sources, 114 (17.0%) heard from the media while only 35 (5.2%) heard from health workers. Out of the 1,028 respondents screened for HAT, 28 were CATT positive, seroprevalence of 2.7%, 19 (67.9%) had knowledge of HAT symptoms, 22 (78.6%) had knowledge of mode of transmission, 12 (42.9%) had knowledge of personal protection from tsetse flies and only 2 (7.1%) had knowledge of how to seek care. Analysis involving two variables (bi-variate analysis) showed that respondents of who know how to seek care were less likely to be sero positive to HAT (p = 0.02). Seropositivity to HAT infection was lower among respondents who had knowledge of how to protect themselves from the disease. All the seven villages from seven Local Government Areas chosen through three stage random sampling in the three senatorial districts were mapped and their coordinates taken using the Global Positioning System (GPS) HAT is endemic in Delta State, Nigeria. Prevalence rate was low but sero positive persons had high titres for CATT for T.b. gambiense. Risk factors for infection included ignorance about where to seek medical care when ill with HAT and knowledge about personal protection against HAT. Mass health education on preventive measures for HAT should be embarked upon and health care providers should be sensitized, for improved suspicion index for HAT diagnosis and management in Delta State and Nigeria.