Chronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg- or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT and AST. In comparison with the HC, fewer CD3(-) CD56(+) and CD244(+) NK cells and CD3(+) CD8(+) T cells, lower frequencies of cytokine(+) CD4(+) T cells, and more CD3(+) CD4(+), CD4(+) CD25(+) Foxp3(+), CD4(+) CD25(+) CD127(low), and CD8(+) PD-1(+) T cells were detected in CHB patients. Treatment with LDT increased the numbers of NK and CD8(+) cells and the frequencies of cytokine(+) CD4(+) T cells but reduced the numbers of CD4(+) CD25(+) Foxp3(+), CD4(+) CD25(+) CD127(low), and CD8(+) PD-1(+) T cells in CHB patients. The frequencies of cytokine(+) CD4(+) T cells were negatively associated with the levels of serum HBV DNA, ALT, and AST. Thus, treatment with LDT inhibits HBV replication, modulates T and NK cell immunity, and improves liver function in Chinese patients with CHB.