Background: Serum alaninc aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hcpatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes. Methods: A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval. Results: Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-gamma-expressing T-helper cells were increased in patients with host-induced ALT increases. Conclusions: Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes.