This thesis traces the profound effect of disease and sickness upon the political economy and culture of the slave plantation system of the antebellum US South between 1803 and 1860. Specifically I explore the Lower Mississippi Valley area of the region, sometimes referred to as the ‘Cotton Kingdom.’ At the project’s heart is the question of how the region’s disease ecology, and the measures employed to combat it, shaped the development and the contours of Southwestern society’s most important institution: racial slavery. Inequality and exploitation were woven into the fabric of slave society, but the growth of the Lower Mississippi Valley’s plantation economy did not take place within a vacuum. The environmental, demographic, and economic conditions necessary to unlock the fertility and wealth of the region also brought settlers—both black and white, enslaved and free—into contact with a tropical disease ecology that was virulent and indiscriminate. Yet disease and sickness remain under-studied components of life in the Cotton Kingdom. For contemporaries, however, sickness was a source of near constant, often obsessive, speculation and fear. With little understanding of epidemiology, no concept of how diseases spread, and few resources to counteract its effects, Southwesterners of all stripes unsurprisingly believed themselves to be at the perilous mercy of illness and death. That reality profoundly shaped Southwestern society. In the eyes of planters it vindicated the expansion of slavery and bolstered a pro-slavery movement which increasingly used white vulnerability to defend the mass enslavement of supposedly less-vulnerable African Americans. It brought contingency and unpredictability onto plantations. And it shaped relations between enslavers and the enslaved, bringing highly charged questions about bodily autonomy, medical determinism, and the imperatives of adequate healthcare to the fore.