Background: Common variable immunodeficiency (CVID) is characterized by an impaired post-vaccination response, high susceptibility to respiratory tract infections, and a broad spectrum of non-infectious complications. Thus, patients with CVID are at high risk of coronavirus disease 2019 (COVID-19), and vaccination’s role in prevention is questionable. The main aim of this study was to evaluate the clinical outcomes, safety, and dynamics of humoral and T-cell immune responses induced by the mRNA vaccine BNT162b2 in CVID. Methods: This prospective observational cohort study focused on the clinical outcomes (proportion of infected patients, disease severity), safety (adverse-event incidence, laboratory-parameter changes), and dynamics of humoral (specific post-vaccination and virus-neutralizing-antibody assessment) and T-cell immune responses (anti-SARS-CoV-2 specific T-cell detection) in 21 patients with CVID after a two-dose administration of BNT162b2. The patients were followed for 6 months. Results: Humoral response was observed in 52% (11/21) of patients at month 1 post-vaccination but continuously decreased to 33.3% (5/15) at month 6. Nevertheless, they had a remarkably lower anti-SARS-CoV-2 neutralizing antibody titer than healthy controls. The T-cell response was measurable in 33% (6/17) of patients with CVID at month 1, and it persisted for the study period. Mild infection occurred in three patients (14.3%) within the follow-up period. The vaccine also exhibited a favorable safety profile. Conclusions: The BNT162b2 vaccine elicited a measurable antibody response in a high proportion of patients, but it was limited by low titer of the virus-neutralizing antibodies and rapid waning of anti-RBD SARS-CoV-2 specific antibodies. T-cell response was detected in one-third of the patients and remained stable within the follow-up period. Vaccination has favorable safety and clinical-related outcomes in preventing severe COVID-19.