Hepatitis B virus (HBV) is intrinsically immunogenic, with long-lasting immune control in many patients. However, the mechanisms and key cell types underlying effective immune control are incompletely understood. We studied the restoration of natural killer (NK) cell numbers and function post antiviral treatment in 52 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who received telbivudine (LdT) for 48 weeks. Blood samples were collected at week 0, 12, 24, 36, and 48 and tested for HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, liver enzymes, and NK cell parameters. Compared with baseline, the number of peripheral CD3(-)CD56(bright) NK cells increased significantly from week 24 to 48, especially in patients with baseline alanine transaminase (ALT) two- to fivefold the upper line of normal (ULN) or HBV DNA < 9 log(10) copies/ml. Expression (number and density) of activating receptors NKG2D and NKp46 on CD3(-)CD56(bright) NK cells was enhanced, while inhibitory receptor NKG2A decreased. Notably, numbers of CD3(-)CD56(bright) or NKG2D(+)CD3(-)CD56(bright) NK cells were significantly better restored in patients with HBeAg seroconversion. NK cell activating serum interleukin 15 (IL-15) was significantly increased during LdT treatment, especially in HBeAg seroconverters. LdT significantly enhanced expression of NKG2D and IL-15 in cultures of purified peripheral NK cells from treatment-na < ve HBeAg-positive CHB patients. Functional restoration of CD56(bright) NK cells via upregulation of IL-15 and NKG2D is a novel activity of LdT and likely other antivirals, independent of its effect on HBV replication. This also demonstrates the importance of host immune restoration in controlling chronic HBV infection.