Vaccines are the most successful strategy developed in Medicine to prevent and even eradicate the most dreadful epidemic infectious diseases. The history of smallpox vaccination in Naples is quite unique. Although Galbiati established the retro-vaccination (1803) and developed the "calf" lymph vaccine, recognized and implemented since 1864 as the optimal smallpox vaccine in the following hundred years, Naples general population was mainly vaccinated with "human" lymph from abandoned children until 1893. Mini-epidemics of syphilis and serum hepatitis were periodically reported as results of arm-to-arm procedure. The risk of transmission of blood-related pathogens was higher in Naples where >80% of abandoned children, used as repository of cowpox virus, were dying in their first year of life. Recent vaccinology standards finally eliminated the risk of adventitious contaminating pathogens. Implementation of hepatitis B vaccination since 1991 eventually contributed to current HBV prevalence in Campania region <1%, within the range of the European Countries.