Background: Coranavirus disease 2019 (COVID-19) has affected more than 220 millon people worldwide. The establishment of safe and effective vaccine coverage is crucial in these patients. We aim to investigate the safety, adverse effects and immune response (cellular and humoral) in cancer patients under active treatment and risk criteria. Methods: 56 samples from cancer patients under active treatment for cancer were collected before and after vaccination Demographic, clinical and biochemical data were collected and a post-vaccination symptomatology questionnaire was performed. For the determination of anti-SARS-Cov-2 antibodies (Immunoglobulin G and immunoglobulin M) we used the ELISA technique (LIASON SARS-CoV-2 S1/S2 IgG test and LIASON SARS-CoV-2 IgM test, DiaSorin, Saluggia, Italy). A study of the lymphocyte population was performed by flow cytometry. Results: We enrolled 52 patients with cancer who received mRNA vaccines (mRNA-1273 and BNT162b2), 2 patients with AZD1222vaccine and 2 with Ad26.COV2.S vaccine. All patients were SARS-COV-2 naive as determined by a negative anti-SARS-COVID-2 IgG test baseline. The median follow-up time was 50 days after receip of a second vaccine dosis. All subject received anti- cancer therapy. The most common anti-cancer treatment received by this cohort of patients was cytotoxic chemoterapy (44.6%), immunotherapy (25%), and monoclonal antibody therapy (14.3%). Overall, a high rate of seroconvertion(anti–IgG) (94,5%) was observed in our cohort, 1 patients with chemotherapy (1,8%) and 2 patients with immunotherapy (3,6%) were negatives. No significant differences in antibody titer were observed according to therapy. Thirty percent presented an antibody titer lower than 1000 U/ml, 27 (48%) patients developed an anti-SARS-CoV2 titer between 1000-4000 U/ml, and only 9 (16%) subjects presented a titer higher than 4000 U/ml. Studies of the lymphocyte profile of vaccinated patients showed no significant changes in the subtypes, except for peripheral memory CD3+ CD8+ lymphocytes which were significantly increased (p = 0.0001) after the second dose of anti-SARS-CoV-2 vaccine. Interestingly, cell apoptosis was significantly reduced in almost all T lymphocyte subtypes studied in vaccinated patients. Finally, analysis of blood cells showed a statistically significant increase (p = 0.0402) of eosinophils in vaccinated patients compared to baseline data. Conclusions: A personalized approach to vaccination can be proposed to cancer patients, especially depending on the type of tumor and the specific oncological treatments received. We are currently recruiting patients (n = 150) who have received the third dose of vaccine and plan to follow up at 6 months for humoral and cellular immune response. Final results will be reported at the ASCO meeting.