Background The association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied. Methods Our observational cohort study included 166, 256 adult KTRs in 2000-2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (death); and the HR of the composite outcomes of NMSC or death and SOM or death associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1-3, and 4-6 HLA-mm subgroups. Results NMSC risk was lower with MTORI than non-MTORI in all HLA-mm groups [(0 mm, HRcs = 0.67; 95% CI = 0.46-0.97, 1-3 mm, HRcs = 0.73; 95% CI = 0.61-0.87, 4-6 mm, HRcs = 0.69; 95% CI = 0.62-0.76)]. SOM risks were similar between regimens in the 0 HLA mm groups (HRcs = 1.10 (95% CI = 0.78-1.57) and lower with MTORI than non-MTORI in the 1-3, and 4-6 HLA-mm groups, [(HR = 0.84; (95% CI = 0.71-0.99), and (HR = 0.86; 95% CI = 0.78-0.94); respectively]. Risks of death and composite outcomes (NMSC or death and SOM or death) were higher with MTORI than non-MTORI in almost all HLA-mm groups. Conclusion MTORIs are associated with protection from NMSC and SOM in almost all HLA-mm groups; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.Copyright © 2021. Published by Elsevier B.V.