SARS-CoV-2 is a betacoronavirus, which induced a severe pandemic infectious disease around the world. Even if several drugs have been suggested for its treatment, to date, the only strategy to reduce the severity of disease is represented by the use of vaccine. However, the lack of pre-marketing evidence in frail patients suggests the necessity of the real-world study of a vaccine benefit–risk profile. In this study, we evaluated the efficacy and the safety of SARS-CoV-2 vaccination in a cohort of 33 patients treated with an immunosuppressant after solid organ transplant. Both CLIA and LS/MS analysis were used to evaluate the levels of immunoglobulin (Ig)G anti SARS-CoV-2 and the therapeutic drug monitoring of immunosuppressant drugs. We documented that SARS-CoV-2 vaccination induced a dose- and gender-related serological response. In particular, in 63.6% of the enrolled patients, we documented a significant serological response at T2, and after a time related decrease, the booster dose induced a serological response in 72.7% of enrolled patients. In conclusion, the vaccine anti SARS-CoV-2 is immunogenic in patients under immunosuppression, and is not related to the development of ADRs. We also suggest that the booster dose could be used to increase the efficacy of the vaccination, particularly in women.