Here, we provide an analysis on 1996-2016 St. Petersburg tick-borne encephalitis (TBE) epidemiological and ecological data. In particular, two main TBE transmission vectors were observed in St. Petersburg: I. persulcatus and I. ricinus. TBE tick contamination was 0.61% as shown by ELISA and polymerase chain reaction data. It is found that number of subjects seeking for medical aid due to tick bites rises, whereas TBE incidence declines. In particular, a mean 1996-2002 vs. 2010-2016 tick-bite incidence rate increased from 141.9 up to 288.9, respectively. Despite that the Leningrad region is a major area for TBE spread, however, a risk of exposure to tick bites as well as TBE infection exists even in the city of St. Petersburg. In connection with this, around 1,000 subjects undergo tick bites within the city limits. Moreover, whereas a 1996-2002 mean TBE incidence rate was 1.66, it decreased in 2010-2016 down to 1.17. A peak TBE incidence was documented in St. Petersburg Kurortny, Pushkinsky and Primorsky districts. In addition, males vs. females suffered from TBE at higher frequency in Russian Federation, with its peak incidence rate being reported in children under 14 that differs St. Petersburg from the most of other regions in the Russian Federation. A seasonal distribution of TBE cases in St. Petersburg does not differ from that one for the remainder of Russian regions, which displays a spring-summer seasonality lasting from April to September. Of note, 1996-2016 St. Petersburg TBE mortality was 1.37%. A coverage of TBE vaccinated population tends to rise but still remains at low level (0.25-0.58%). Lack of reported TBE cases in occupationally threatened human cohorts evidences about efficient preventive measures. Detection of TBE virus-specific serum antibodies in 5.0% apparently healthy and unvaccinated residents in St. Petersburg significantly complements the official TBE recording data and provides a more accurate understanding of its actual spread.