Even today, healthcare-associated infections (HCAIs) remain the most frequent and serious complications in healthcare, with a significant clinical and economic impact. The authors of this manuscript address the causes and conditions that determine this situation and describe them in comparison with the situation in the Grand Duchy of Tuscany more than two centuries ago and with the instructions that were issued at the time to contain the typhus epidemic of 1817, increase hospital sanitation, and disinfect houses. Today, we know that a crucial element in the fight against healthcare-associated infections (HCAIs) is the definition and implementation of best care practices and other measures, according to a combined program that must be tailored to each healthcare setting. In the early nineteenth century, these approaches originated from experience and chemical knowledge that were becoming established, opening the way to the ideas and experiments of Ignác Fülöp Semmelweis and later of Joseph Lister, who traced the path for the birth of hygiene. Two centuries later the pioneering vision of the Grand Duchy of Tuscany at the beginning of the 19th century, when preventive measures in the field of public health were still backward and underdeveloped, is still enlightening and surprisingly topical.