Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV-based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed-effects model. HBV DNA levels were also compared between the five groups during the 96-week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV-based combination or single therapies.