The Antonine Plague, which flared up during the reign of Marcus Aurelius from 165 AD and continued under the rule of his son Commodus, played such a major role that the pathocenosis in the Ancient World was changed. The spread of the epidemic was favoured by the occurrence of two military episodes in which Marcus Aurelius himself took part: the Parthian War in Mesopotamia and the wars against the Marcomanni in northeastern Italy, in Noricum and in Pannonia. Accounts of the clinical features of the epidemic are scant and disjointed, with the main source being Galen, who witnessed the plague. Unfortunately, the great physician provides us with only a brief presentation of the disease, his aim being to supply therapeutic approaches, thus passing over the accurate description of the disease symptoms. Although the reports of some clinical cases treated by Galen lead us to think that the Antonine plague was caused by smallpox, palaeopathological confirmation is lacking. Some archaeological evidence (such as terracotta finds) from Italy might reinforce this opinion. In these finds, some details can be observed, suggesting the artist's purpose to represent the classic smallpox pustules, typical signs of the disease. The extent of the epidemic has been extensively debated: the majority of authors agree that the impact of the plague was severe, influencing military conscription, the agricultural and urban economy, and depleting the coffers of the State. The Antonine plague affected ancient Roman traditions, also leaving a mark on artistic expression; a renewal of spirituality and religiousness was recorded. These events created the conditions for the spread of monotheistic religions, such as Mithraism and Christianity. This period, characterized by health, social and economic crises, paved the way for the entry into the Empire of neighbouring barbarian tribes and the recruitment of barbarian troops into the Roman army; these events particularly favoured the cultural and political growth of these populations. The Antonine Plague may well have created the conditions for the decline of the Roman Empire and, afterwards, for its fall in the West in the fifth century AD.