Post-marketing safety evaluation of flu vaccine during the 2020-2021 flu vaccination campaign in Italy: a Self-Controlled Case Series study of Guillain-Barré syndrome Introduction The Istituto Superiore di Sanità and the Agenzia Italiana del Farmaco coordinate the project TheShinISS-Vax|Flu, a post-marketing “active” surveillance of influenza vaccines. We report the results of the investigation using the Self-Controlled Case Series (SCCS) design on influenza vaccine and Guillain-Barré syndrome in vaccinated population aged over than 6 months, during the influenza vaccine campaign 2020-2021 in Italy. Materials and methods A SCCS multi-regional study was carried out using linked data from Regional Health Care Registries of Valle d’Aosta, Friuli Venezia Giulia, Emilia-Romagna, Toscana, Lazio, Campania, and Puglia. Relative incidence of Guillain-Barré syndrome was estimated, comparing the exposure risk periods (0-41 days from the vaccination day, subdivided in six intervals) with the unexposed period. Results Among 5,804,630 vaccinated subjects, 100 events of Guillain-Barré syndrome were observed during the study period, and 31 events occurred in the 42-day period following the administration of influenza vaccine. Within the second and third week following vaccination, an association was found with relative incidence of 2.76 (95% CI 1.41-5.38) and 3.03 (95% CI 1.59-5.80) respectively, corresponding to a number of excess cases of 0.11 (0.05-0.14) and 0.13 (0.07-0.16) per 100,000 vaccinated. Discussion and conclusions Results from this large SCCS study indicated that influenza vaccination is associated with Guillain-Barré syndrome, but that events are rare. Influenza vaccination remains a valid preventive measure to respond to an important public health problem, taking into account that influenza is a risk factor for both Guillain-Barré syndrome and other well-known complications, such as hospitalization and mortality. Key words: influenza vaccines; Guillain-Barré syndrome; post marketing surveillance