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Sophocles, one of the most noted playwrights of the ancient world, wrote the tragedy Oedipus Rex in the first half of the decade 430–420 bc. A lethal plague is described in this drama. We adopted a critical approach to Oedipus Rex in analyzing the literary description of the disease, unraveling its clinical features, and defining a possible underlying cause. Our goals were to clarify whether the plague described in Oedipus Rex reflects an actual historical event; to compare it with the plague of Athens, which was described by Thucydides as occurring around the same time Sophocles wrote; and to propose a likely causative pathogen. A critical reading of Oedipus Rex and a comparison with Thucydides’ history, as well as a systematic review of historical data, strongly suggests that this epidemic was an actual event, possibly caused by Brucella abortus.