Smallpox is a contagious viral disease. In the fight against smallpox, stimulation of the immune system by means of inoculation of human smallpox and subsequent vaccination constituted a very important step forward in the history of medicine. First reported in ancient Greece and in the Egypt of the Pharaohs, smallpox reappeared in the middle of the 16th century, becoming the leading endemic disease in the following century and periodically causing hundreds of thousands of deaths. In the 18th and 19th centuries, Europe was afflicted by numerous epidemics. While their consequences in large urban centres are well known, we know little about the diffusion, morbidity and mortality of the disease in rural areas. To shed light on this issue, we scrutinised the main initial experiences of the use of inoculation in Siena and the scientific, healthcare, social and political consequences that stemmed from them.