The clinical course of patients with chronic hepatitis B (CH-B) was greatly changed by the introduction of nucleoside analogues. We often encounter patients where the serum level of albumin recovers quickly following the treatment. In this study, we focused carefully on the changes in serum albumin level noted during nucleoside analogue therapy, in an effort to clarify the mechanism behind the restoration of albumin production. We observed changes in serum albumin levels during nucleoside analogue therapy in 12 patients with CH-B and studied the mechanism behind the restoration of albumin production following the therapy. The serum level of albumin was significantly increased very soon after the treatment was started. Prior to treatment with nucleoside analogues, the albumin signal for mRNA was only slightly seen in the peri-portal area, whereas 12 months after the treatment, the liver tissue presented an obvious signal of albumin mRNA. Serum levels of hepatocyte growth factor (HGF) were significantly decreased 12 months after the treatment. In this study, we demonstrated that nucleoside analogues decrease HGF through the suppression of hepatocyte damage, leading to the restoration of albumin production in patients with CH-B.