Background: Immune system impairment is frequently reported in patients affected by hemoglobinopathies due to various mechanisms, including iron accumulation, antigenic stimulation due to numerous transfusions, chronic hemolysis, and a general hyperinflammatory state. For these reasons, the antigenic immune response after a vaccine risks being ineffective. Methods: We evaluated the anti-spike IgG production after two doses of vaccine for SARS-CoV-2 in patients affected by hemoglobinopathies. Results: All 114 enrolled patients (100%) developed adequate antibody production, with a median value of serum IgG of 2184.4 BAU/mL (IQR 1127.4–3502.9). The amount of antibody was unrelated to any other clinical characteristics evaluated, including transfusion dependence or non-transfusion dependence, age, gender, disease type, ferritin, blood count, spleen status, and therapy with hydroxyurea or iron chelators (in all the cases p > 0.05). Moreover, 47 (41.2%) patients developed breakthrough SARS-CoV-2 infection during the first 2 years of follow-up after vaccination, all with a mildly symptomatic course, without requiring hospitalization or experiencing a significative drop in hemoglobin values, allowing for a slight delay in their transfusion regimen. Conclusion: Vaccination against COVID-19 is safe and effective for patients affected by hemoglobinopathies, ensuring adequate protection from severe infection.