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Background: Kenya and Uganda have reported different Human African Trypanosomiasis incidences in the past more than three decades, with the latter recording more cases. This cross-sectional study assessed the demographic characteristics, tsetse and trypanosomiasis control practices, socio-economic and cultural risk factors influencing Trypanosoma brucei rhodesiense (T.b.r.) infection in Teso and Busia Districts, Western Kenya and Tororo and Busia Districts, Southeast Uganda. A conceptual framework was postulated to explain interactions of various socio-economic, cultural and tsetse control factors that predispose individuals and populations to HAT., Methods: A cross-sectional household survey was conducted between April and October 2008. Four administrative districts reporting T.b.r and lying adjacent to each other at the international boundary of Kenya and Uganda were purposely selected. Household data collection was carried out in two villages that had experienced HAT and one other village that had no reported HAT case from 1977 to 2008 in each district. A structured questionnaire was administered to 384 randomly selected household heads or their representatives in each country. The percent of respondents giving a specific answer was reported. Secondary data was also obtained on socio-economic and political issues in both countries., Results: Inadequate knowledge on the disease cycle and intervention measures contributed considerable barriers to HAT, and more so in Uganda than in Kenya. Gender-associated socio-cultural practices greatly predisposed individuals to HAT. Pesticides-based crop husbandry in the 1970's reportedly reduced vector population while vegetation of coffee and banana's and livestock husbandry directly increased occurrence of HAT. Livestock husbandry practices in the villages were strong predictors of HAT incidence. The residents in Kenya (6.7%) applied chemoprophylaxis and chemotherapeutic controls against trypanosomiasis to a larger extent than Uganda (2.1%)., Conclusion: Knowledge on tsetse and its control methods, culture, farming practice, demographic and socio-economic variables explained occurrence of HAT better than landscape features.