Entecavir (ETV) has been used for more than 2 decades in treating hepatitis B virus (HBV) infections. It has shown significant anti-HBV effect and has led to histological improvement in the liver of chronic hepatitis B (CHB) patients. In patients treated with ETV for over two years, reversal of cirrhosis to normal tissue has also been observed. However, the mechanisms of these tissue repairing or recovery processes are not yet clear. In order to determine the roles that bone marrow and liver stem/progenitor cells play in these processes, we evaluated the CD34(+) and CD133(+) stem/progenitor cells in peripheral blood from 292 patients and liver tissues from 43 patients who had received therapies with and without ETV. A significant increase in both CD34(+) and CD133(+) cells was found in CHB and cirrhosis patients compared to the healthy controls. In patients treated with ETV, CD34(+) cells increased 2 and 4 fold in peripheral blood and liver tissues, respectively, while their CD4(+) and CD8(+) cells remained the same. On the other hand, CD133(+) cells did not change or even slightly decreased with ETV treatment. Results from immunohistochemistry staining, real time RT-PCR, and the enzyme-linked immunosorbent assay also revealed the same level of CD34(+) cell increase and CD133(+) cell decrease (or no change) in ETV treated patients, compared to patients without ETV therapies. Liver functions in patients with ETV treatment improved in general, but one liver cirrhosis patient with high expression of CD133 in liver tissue developed hepatocellular carcinoma (HCC). In summary, ETV may have differential effects on various stem cell subtypes. ETV-activated stem cells in bone marrow and liver tissues may contribute to the recovery from injuries caused by HBV infection. They also contribute to the regeneration of normal tissue and the recovery of normal liver function. Meanwhile, ETV does not activate stem cells that may participate in the initiation of HCC.