The epidemiological situation on West Nile fever (WNF) in Russia in 2021 was characterized by an increase in the incidence relative to 2020 (more than 6-fold increase). The peculiarities of the WNF epidemic process have been determined: the territorial distribution of cases (75 % – in the constituent entities of the Central Federal District), the expansion of the causative agent’s areal with the involvement of new territories (official registration of cases in Moscow and the Tula Region for the first time ever), the early end of the epidemic season. An increase in the proportion of neuroinvasive forms, an increase in the share of male patients and the age group of 30–39 years, a decrease in the proportion of the population in contact with the pathogen in natural places of mass recreation were observed in the incidence structure. According to the results of the monitoring studies carried out by the Reference Center, intensive circulation of the pathogen was established on the territory of the Central Federal District, Southern Federal District, and the North Caucasian Federal District. The low reported incidence was due to insufficient detection of WNF patients. The results of moleculargenetic study showed that in the European part of Russia, WNV lineage 2 circulated in both epizootic and epidemic cycles, lineage 2 in the south of Western Siberia (Omsk Region) and lineage 4 in the Volgograd Region – in the epizootic cycle only. Phylogenetic analysis revealed that strains isolated from the Astrakhan, Volgograd, Rostov, Voronezh Regions and the Republic of Dagestan in 2021 belong to the genovariant of WNV lineage 2 not registered in Russia previously. The topology of the phylogenetic tree indicates the possible African origin of the isolates, probably imported into Russia by migratory birds across the coast of the Caspian Sea. In the Volgograd Region, WNV of both the entrenched clade of lineage 2 (since 2007) and new genovariant circulated. The specialists of the Reference Center developed a forecast of WNF epidemiological situation development in the Volgograd Region in 2022 on the basis of the neural network modeling technique, according to which an increase in the incidence is expected, comparable to that in 2010 and 2012. Based on the climate projections, an increase in the incidence is possible in all Federal Districts of the European part of Russia, the southern territories of the Urals, Western Siberia, and the Far East.