Tenofovir disoproxil fumarate (TDF) therapy is a therapeutic option for nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV). In this study, we evaluated the efficacy of TDF alone compared with the efficacy of TDF plus additional NA combinations in NA-experienced CHB patients. This retrospective cohort study included 108 patients with a serum HBV DNA level above 5.0 log10 IU/ml who were treated with TDF alone (monotherapy group) or TDF combined with additional NAs (combination therapy group) for 30months. At month 30, both therapies resulted in the suppression of HBV DNA levels: 66 of 66 patients (100%) in the monotherapy group and 40 of 42 patients (95.23%) in the combination therapy group achieved virologic suppression. Kaplan-Meier curves revealed median times for virologic suppression of 3.12months in the monotherapy group and 5.23months in the combination therapy group (p=0.699). The probability of virologic suppression was comparable between treatment groups. At month 6, more patients achieved normal alanine aminotransferase (ALT) levels in the monotherapy group (p=0.029). During the treatment period, no patients experienced severe renal dysfunction. TDF monotherapy and TDF plus additional NAs have comparable antiviral efficacy in CHB patients after NA treatment failure.