In the 1830s, plague, which was all but forgotten by most Europeans, was on everyone’s lips again. Following devastating outbreaks of plague in the Levant and the Nile Delta, the Ottoman and Egyptian governments instituted their first permanent quarantines, adopting the quarantine model long practiced in the western parts of the Mediterranean. The global medical community anxiously watched whether the new quarantines would be able to contain plague, as well as cholera, within the Eastern Mediterranean. By tracing two tsarist medical expeditions from the Black Sea port of Odessa to the Ottoman Empire and Egypt in the 1840s, this paper examines the little-known world of European doctors and quarantine specialists, residing or traveling in Ottoman and Egyptian domains, who engaged in vigorous debates about plague and its prevention. Did plague have a birthplace somewhere in the Middle East? Did plague spread through contact with plague victims, or was the contagion omnipresent in the bad air? Russian, French, British, Austrian, and other medics questioned old assumptions about plague, while testing out their hypotheses in Middle Eastern environments. This paper demonstrates that, by the mid-nineteenth century, the Middle East became a global focus for epidemiological research, driving the internationalization of anti-epidemic prevention. Meanwhile, the efficiency of Egyptian and Ottoman quarantines, and with it the nature of plague, were engrossed with European political ambitions and commercial interests in the Middle East.