Abstract Background and Aims Induction therapy plays a key role in the prevention of 1-year acute rejection in kidney transplantation. Several studies suggest that depleting drugs, including thymoglobulin (ATG), are superior to anti-CD25 antibodies in reducing the incidence of acute rejection. However, large retrospective investigations demonstrate a close and significant association between the use of depleting agents and the development of post-transplant neoplasia, in particular post-transplant lymphoproliferative disease. Thus, in the attempt to improve the risk/benefit profile of antibody therapy, we implemented an induction protocol based on low-dose ATG and anti-CD25 blocker basiliximab (Bas). The aim of the present study was to evaluate the efficacy and safety of this approach compared to standard dose ATG alone and basiliximab alone. Method This is a an observational, retrospective, single center study including 957 patients receiving a single kidney transplant the Gemelli kidney transplant center from January 2000 to February 2022 The primary efficacy outcome was biopsy proven acute rejection and the primary safety outcome was the development of post-transplant neoplasia. Patients in the ATG group received a cumulative dose of 7mg/kg in the first week after transplantation; patients in the Bas group were administered the anti-CD25 antibody at a dose of 20 mg before surgery and 20 mg 4 days after transplantation. Finally, patients in the ATG-Bas group received ATG at a cumulative concentration of 3mg/kg over the first 6 days after transplantation and Bas at a dose of 20 mg before surgery and 20 mg 4 days after transplantation. Results In our study population we evaluated 154 patients in the standard ATG group, 492 patients in the low AATG-Bas group and 311 patients in the Bas group. No statistical difference for age, mismatches, donor type, donor age, pre-transplant PRA was observed among groups. Use of mTOR inhibitors was more frequent in the standard ATG and low ATG-Bas groups compared to Bas group (80/154, 155/492, 76/311, respectively, p<0.001). We did not observe any significant difference in the use of other maintenance immunosuppressive drugs. Multivariate analysis (Cox model, including number of mismatches, presence of DSA at transplantation and use of mTOR inhibitors) demonstrated that only low ATG-Bas treatment (HR 0.509 95%CI 0.344-0.754, p<0.001), but not standard ATG (HR 0,819 95%CI 0.472-1.423, p = 0.5), was able to reduce the risk for acute rejection compared to Bas alone. On the other hand, multivariate analysis (Cox model including acute rejection, age, use of mTOR inhibitors) demonstrated that standard ATG induction (HR 1.677 95%CI 1.035-2.717, p = 0.03), but not low ATG-Bas (HR 1,324 95%CI 0,930-1,884, p = 0.1), significantly increased the risk for the development of post-transplant neoplasia compared to Bas alone. Conclusion In this retrospective analysis we demonstrated that low ATG-Bas protocol was the most effective treatment in preventing biopsy-proven acute rejection. In addition, on the contrary of standard ATG dose protocol it did not increase the risk of post-transplant neoplasia compared to Bas alone induction therapy.