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In August 2022, Italy launched a vaccination campaign to combat the spread of the monkeypox virus, which the WHO has designated as a public health emergency. Priority targets for the campaign included laboratory personnel and men who have sex with men with specific risk criteria. Primary immunization involved two doses of the Imvanex/Jynneos vaccine, followed by a single booster dose. We conducted a study in two Italian towns, Bologna and Forlì, in October and November 2022 to investigate adverse events following immunization (AEFIs) of the monkeypox vaccine through participant-based active surveillance. Participants who received the vaccine and were aged 18 and over were invited to complete an e-questionnaire by scanning a QR code during their second vaccine appointment or by email one month after the booster dose. A descriptive analysis of AEFI incidences was conducted, with the results stratified by type and severity of symptoms. A total of 135 first-dose, 50 second-dose, and 6 single-dose recipients were included, with a mean age of 36.4 ± 8.7 years. Systemic reactions after the first and second doses were reported by 39.3% and 26.0% of participants, respectively, with asthenia being the most common symptom. Local site reactions were reported by 97.0% and 100.0% of participants, respectively, with redness, swelling, and itching being the most common local AEFIs. Grade 3 or 4 AEFIs were reported for local AEFIs only by 16.8% and 14.0% of participants after the first and second doses, respectively. Our findings suggest that the monkeypox vaccine has a high tolerability profile in terms of short-term common systemic AEFIs. However, the high incidence and severity of local AEFIs highlight the need to monitor their persistence following intradermal administration of the vaccine. [ABSTRACT FROM AUTHOR]