The article is devoted to the initial period in the history of vaccination against smallpox in Russia. Since 1811, vaccination against smallpox became nationwide, however, its effectiveness varied from gubernia to gubernia. Modern scientific literature focuses on the anti-epidemic activities of the second half of the 19th century. One of the little-studied subjects is the vaccination against smallpox in the St. Petersburg and Moscow gubernias in the first quarter of the 19th century. For a long time, smallpox was one of the major factors of mortality in Russia. The study of the organization of vaccination in 1811-1820 in the St. Petersburg and Moscow gubernias, which had a special status, is important for comprehensive analysis of the development of national medicine and identification of major factors in gradual change in mortality rates. The source base is reports sent to the Ministry of Internal Affairs by the Moscow civil governor and St. Petersburg medical board (Physicut), as well as reports of the uezd doctors. These documents are being thus introduced into scientific use. Statistical methods for processing mass sources are applied and relational databases created. The article discusses absolute and relative indicators characterizing the success of vaccination in each gubernia and characterizes the organization of the smallpox vaccination: its regularity, equal distribution in the uezds, personnel.