This article reconstructs the first outbreak of epidemic dropsy recorded in documentary evidence, which occurred in Calcutta, Mauritius, and northeastern India and Bengal in 1877–80. It uses current medical knowledge and investigations into the wider historical contexts in which the epidemic occurred to re-read the colonial medical literature of the period. It shows that colonial policies and structures in the context of variable enviro-climatic conditions increased the likelihood that an epidemic would break out, while also increasing the vulnerability of certain populations to infection and mortality. Additionally, it shows how the trans-regional nature of the epidemic contributed to varying understandings of the disease between two colonial medical establishments, which influenced each other in contradictory ways. The article’s core contributions are to recent trans-regional perspectives on disease transmission and colonial medical knowledge production in the Indian Ocean World.