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Background: Long-term data on COVID-19 vaccine safety, immunogenicity, and acceptance in adults with CHD are lacking. Methods: This is a prospective study including adults with CHD patients undergoing COVID-19 vaccination from January 2021 to June 2022. Data on adverse events, antispike IgG titre, previous or subsequent COVID-19 infection, booster doses, and patients’ attitude towards vaccination were collected. Results: Four hundred and ninety CHD patients (36 ± 13 years, 53% male, 94% with moderate/complex defects) were prospectively included: 433 (88%) received a Pfizer–BioNTech mRNA vaccine, 31 (6%) Moderna mRNA vaccine, 23 (5%) AstraZeneca–Oxford ChAdOx1 nCov-19 vaccine, and 3 (0.6%) Janssen Vaccine; 310 (63%) received a booster dose. Median follow-up after vaccination was 1.53 [1.41–1.58] years. No major adverse event was reported. Eighty-two fully vaccinated patients contracted COVID-19 during follow-up after a median of 5.4 [4.3–6.5] months from the last dose. One patient with Ebstein’s disease died from severe COVID-19. Symptoms’ duration in patients who tested positive after vaccination was significantly shorter than in the group tested positive before vaccination (5.5 [3–8] versus 9 [2.2–15] days, p = 0.04). Median antispike IgG titre measured in 280 individuals (57%) at a median of 1.4 [0.7–3.3] months from the last dose was 2381 [901–8307] BAU/ml. Sixty patients (12%) also showed positive antinucleocapsid antibodies, demonstrating previous SARS-COV2 exposure. Twenty-nine percent appeared to have concerns regarding vaccine safety and 42% reported fearing potential effects of the vaccine on their cardiac disease before discussing with their CHD cardiologist. Conclusion: COVID-19 vaccines appear safe in the mid-term follow-up in adults with CHD with satisfactory immunogenicity and reduction of symptoms’ duration in case of infection.