Influenza, acute upper respiratory tract infections (AURIs) and severe acute respiratory infections (SARIs) are the most common infectious diseases worldwide. Global monitoring of antigenic variations of influenza viruses is essential for detecting the emergence of new epidemic and pandemic strains. Frequent antigenic variations require periodic updates of vaccines to match new variants emerging during influenza epidemics and the use of data to improve the influenza vaccine component as well as testing the sensitivity of antiviral preparations sensitive to Oseltamivir and Zanamivir. Epidemiological features of the evolution of influenza, AURIs and SARIs, depending on the phenotypic and genotypic characteristics of the dominant and codominant strains of influenza A(H1N1) pdm09, A(H3N2) and B in the Republic of Moldova, based on the routine and sentinel epidemiological surveillance system. The results obtained allowed to improve the surveillance and response measures for influenza, acute upper respiratory tract infections and severe acute respiratory infections manifested by reducing the incidence of morbidity and mortality from the aforementioned infections, in the group at increased risk of infection. The presence of influenza viruses was significant, with a predominance of the A(H1N1)pdm09 virus in the 30–64 age group and of the A(H3N2) and B viruses in children aged 5–14 years. The isolated influenza virus strains were similar to those included in the vaccine cocktail recommended by the WHO, being sensitive to Oseltamivir and Zanamivir. Among comorbidities, renal infections are in third place, preceded by cardiovascular and respiratory ones. All cases of death are unvaccinated patients.