Kidney transplant (KT) is the optimal renal replacement therapy for patients with end-stage renal disease (ESRD). The demand for kidneys, however, continues to exceed the supply. To overcome this problem, efforts to extend the donor pool by including human leukocyte antigen (HLA)- and ABO-incompatible (ABOi) KTs are increasing. The aim of this article was to retrospectively review data on recipients, donor profiles, and clinical outcomes in 4000 cases of KT. In addition, we analyzed clinical outcomes in ABOi and flow-cytometric crossmatch (FCXM) positive KT in a subgroup analysis.This was a retrospective, observational study using data extracted from medical records. A total of 4000 consecutive patients who underwent KT at our institution from January 1990 to February 2015 were included in this study. KTs across immunological barriers such as ABO incompatible (276 cases, 6.9%), FCXM positive (97 cases, 2.4%), and positive complement-dependent cytotoxicity (CDC) XM KT (16 cases, 0.4%) were included.From a Kaplan-Meier analysis, overall patient survival (PS) rates after KT at 1, 5, 10, and 20 years were 96.9%, 95.1%, 92.0%, and 88.9%, respectively. The overall graft survival (GS) rates after KT at 1, 5, 10, and 20 years were 96.3%, 88.9%, 81.2%, and 67.4%, respectively. Our subgroup analysis suggested that overall PS, GS, death-censored GS, and rejection-free GS in ABOi KT showed no significant differences in comparison with ABO-compatible KT if adequate immunosuppressive treatment was performed. The overall PS rate in patients who underwent FCXM positive KT did not differ significantly from that of the control group during the 3-year follow-up (P = 0.34). The overall GS, death-censored GS, and rejection-free GS also did not differ significantly between the FCXM KT and control groups (P = 0.99, 0.42, and 88).The outcomes of KTs continually improved during the study period, while the annual number of KTs increased. ABO or FCXM positive KTs can be performed safely with successful graft outcomes.