Among hepatitis B surface antigen (HBsAg)-positive renal allograft recipients, post-transplant immunosuppression is associated with the occurrence of hepatocellular carcinoma (HCC) and liver-related complications. Lamivudine has proven beneficial in short-term post-transplant follow-up. We first investigated whether lamivudine is beneficial in reducing both the occurrence of HCC and long-term complication rates among HBsAg-positive renal allograft recipients. We analyzed 26 adult HBsAg positive renal allograft recipients received lamivudine prophylaxis (Group 1-1) and another 28 patients received therapeutic lamivudine (Group 2) due to post-transplant hepatitis B reactivation (Between 2000 and 2009). The historical control group included 43 HBsAg-positive renal allograft recipients who did not receive lamivudine therapy (Group 3). In the series, no subjects in Group 1 presented HCC or liver related complications and the 10-year HCC incidence of Group 2 and Group 3was 4.2 and 34 %, respectively. Furthermore, the HCC-free survival rates as well as the 10-year patient and graft survival rates of Group 1-1 and Group 2 were significantly higher than those of Group 3. However, the rates of liver-related complications and graft rejection of Group 2 and Group 3were both higher than those of Group 1. Additionally, the HBV mutation-free rate of lamivudine was significantly higher in Group 1 than in Group 2. Renal safety is an important factor when selecting the most appropriate NA treatment for HBsAg-positive renal allograft recipients. We then conducted a prospective randomized clinical trial (RCT), HBsAg-positive renal transplant recipients who had received lamivudine prophylaxis for at least 6 months were 1:2 randomized to receive either lamivudine or telbivudine for another 24 months. Renal function was evaluated by creatinine level and estimated glomerular filtration rate (eGFR) at the time of randomization (baseline), 6, 12, 18, and 24 months respectively. However, this RCT was prematurely terminated after recruiting only 17 patients due to a high incidence (61.5%; 8/13) of clinical myalgia in the telbivudine group. Cox’s proportional hazards model revealed that there was no independent predictor of myalgia. Based on intention-to-treat and per protocol analyses using generalized estimating equations, the patients in the randomized telbivudine group had a significantly increased eGFR and the patients in the lamivudine group had a significantly decreased eGFR at the end of follow-up compared to the values at study enrollment. However, there was no significant difference between the lamivudine and telbivudine groups. The cellular immune responses of HBsAg-positive renal transplantation recipients taking immunosuppressants and nucleotide analogues (NAs) are complex and related to the prognosis. We collected blood samples from HBsAg-positive individuals with end-stage renal disease on the transplant waiting list (Group A) and renal transplantation recipients taking immunosuppressants and NAs (Group B) or immunosuppressants without NAs (Group C). Hepatitis B virus (HBV)-specific pentamers were used to quantify circulating HBV-specific CD8+ T cells. Groups B and C had higher cellular immune responses, as indicated by significantly lower regulatory T (Treg)/CD8+ T cell ratios than Group A. With undetectable viral loads under both immunosuppressant and NAs, the CD8+ T cell and HBV-specific CD8+ T cell frequencies were similar in Group B and Group A. Patients in Group C did not use NAs and had an elevated viral load and higher HBV-specific CD8+ T cell and IFN-g-producing HBV-specific CD8+ T cell. Hepatitis B surface antigen (HBsAg)-positive renal transplantation recipients must take lifelong immunosuppressants and nucleotide analogues (NAs). Immunosuppressant therapy increases viral replication in HBsAg-positive renal transplant recipients due to disabling or dysregulation of virus-specific CD8+ T cells. The higher cellular immune responses due to lower Treg/CD8+ T cell ratios in HBsAg-positive renal transplant recipients may be one of the reasons to induce liver pathology because of uncontrolled viral replication. We will investigate the underlying mechanism and clinical applications.