Western Kenya and Southeast Uganda have reported different Human African Trypanosomiasis (HAT) incidences in the past more than 3 decades with the latter recording more cases. Here, we describe interactions between socioeconomics, tsetse dynamics, livestock husbandry and environmental issues at the transboundary of Kenya and Uganda and how they determine Human African Trypanosomiasis (HAT). Comparative studies were carried out in two districts of each country namely Teso and Busia Districts, of Western Kenya and Tororo and Busia Districts, of Southeast Uganda. In addition, primary data was collected in the selected villages for the livestock numbers and human population. Also structured questionnaire was administered systematically to 384 randomly selected household heads or their representatives in each country. Human population density and types of crops grown, livestock numbers and livestock husbandry in the study villages influenced the occurrence of HAT. Prophylactic administration of tyrpanocides and topical application of insecticides on livestock reduced incidence of HAT. Wildlife abundance was high in villages reporting a history of HAT (69%) than HAT free villages (35.5%). The Glossina pallidipes trapped in the study areas sourced their blood meal exclusively from cattle. Therefore livestock keeping practices, wildlife and environmental factors should be incorporated into tsetse and trypanosomiasis control