Mycobacterium ulcerans is sweeping across sub-Saharan Africa, but little is known about the mode of transmission and its natural reservoirs. Since the only effective treatment is excision of the infection and surrounding tissue, early diagnosis and treatment is the only way to reduce the havoc associated with Buruli ulcer. Using data from a national case search survey conducted in Ghana during 2000 and suspected risk factors this study tests the hypothesized factors and probes the challenges of developing a spatial epidemiological regression model to explain Buruli ulcer prevalence in the southwestern region of Ghana representing 42 districts. Results suggest that prevalence is directly related to the degree of land cover classified as soil, elevation differential, and percent rural population of the area.