Two disease regions existed on the Oregon Trail. Asiatic cholera impacted the Platte River flood plain from 1849 to 1852. Dysentery developed two endemic foci due to the decay of buffalo carcasses in eastern and middle Nebraska between 1844 and 1848, but later developed a much larger endemic region west of this Great Plains due to the infection of livestock carcasses by opportunistic bacteria. This study demonstrates that whereas Asiatic cholera diffusion along the Trail was defined primarily by human population features, topography, and regional climate along the Platte River flood plain, the distribution of opportunistic dysentery along the Trail was defined primarily by human and animal fitness in relation to local topography features. By utilizing a geographic interpretation of disease spread, the Asiatic cholera epidemic caused by Vibrio cholerae could be distinguished from the dysentery epidemic caused by one or more species of Salmonella or Campylobacter. In addition, this study also clarifies an important discrepancy popular to the Oregon Trail history literature. "Mountain fever," a disease typically associated with Rocky Mountain Spotted Fever, was demonstrated to be cases of fever induced by the same bacteria responsible for opportunistic dysentery. In addition, several important geographic methods of disease interpretations were used for this study. By relating the epidemiological transition model of disease patterns to the early twentieth century sequent occupance models described in numerous geography journals, a spatially- and temporally-oriented disease model was produced applicable to reviews of disease history, a method of analysis which has important applications to current studies of disease patterns in rapidly changing rural and urban population settings.