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Patients with CLL have high rates of either severe disease or death from COVID-19 and a low response rate after COVID-19 vaccination has been reported. We conducted a single-center study with the main objective to evaluate the immunogenicity of the BNT1162b2 mRNA vaccines in 42 patients affected by CLL with the assessment of antibody response after the second and the third dose. After the second dose of vaccine, 13 patients (30%) showed an antibody response. The presence of hypogammaglobulinemia and the use of steroids or IVIG were the main factors associated with poor response. After the third dose, 5/27 (18%) patients showed an antibody response while in non-responders to the second dose, only 1 patient (4%) showed an elicitation of the immune response by the third dose, with no statistically significant difference. Our data, despite the small size of our cohort, demonstrate that patients with CLL have a low rate of effective response to the BNT162b2 vaccine. However, the effective role of a subsequent dose is still unclear, highlighting the need for alternative methods of immunization in this particularly fragile group of patients.