The efficiency and safety of influenza vaccination were investigated in circulatory system disease (CSD) patients followed up at two Ivanovo polyclinics and two Saratov ones. In each town, one of the polyclinics made active immunization in patients with CSD; the other performed routine one. The investigation enrolled 817 people, including 367 patients who consented to Grippol Plus influenza vaccination and 450 who refused. Mild systemic and local reactions following vaccination were recorded in 4.1 and 3.5% of the cases, respectively; which demonstrates its good tolerability. A 12-month follow-up after being included in the investigation, the vaccinated group showed a significantly fewer infectious diseases than the non-vaccinated group (89 and 223; р<0.0001), among other diseases, acute respiratory viral infection (17 and 50; р<0.0001). The vaccinated group tended to have fewer worsening CSD cases per patient (p=0.25) and CSD-associated hospitalization rates (p=0.13) than the non-vaccinated group. In the vaccinated group, the total number of cases with cerebral stroke, myocardial infarction, deaths from these events, and CSD-associated hospitalizations was significantly smaller (13 and 32; р=0.026). Examination of anti-influenza antibody titer trends in 8 (7.6%) of the 105 non-vaccinated patients revealed serological criteria for prior influenza and the serodiagnostic tests failed to exhibit these cases in 97 vaccinated patients with CSD. Thus, influenza vaccination is an essential component of combination medical prevention in patients with CSD.