Background: Nucleoside and nucleotide analogues (NAs) have a risk of mitochondrial toxicity and then inducing the increase of lactate. We aim to evaluate the impact of lactate on the effects of NAs therapy in hepatitis B virus-related hepatocellular carcinoma (HCC) patients after curative liver resection. Materials and methods: Five hundred and fifty-seven HBV-related HCC patients were divided into the treatment and control group according to whether they received NAs therapy or not. Perioperative and prognosis data were retrospectively reviewed. Results: The treatment group had a better overall survival rate (OS) than the control group (P=0.017). The recurrence-free survival rate (RFS) did not significantly differ between the two groups (P=0.174). NAs could improve the OS of early stage HCC patients (P=0.028), as well as the OS of advanced stage HCC patients with low level of lactate in subgroup analysis stratified against the level of lactate (P=0.037). Advanced stage HCC patients in the treatment group had a higher value of lactate than those in the control group (P= 0.024). Besides, advanced stage HCC patients had a higher value of lactate than early stage HCC patients in the treatment group (P< 0.001), as well as in the control group (P<0.001). Conclusions: NAs could improve the long-term outcomes of HBV-related HCC patients after curative liver resection. However, the improvement effect of NAs therapy is counteracted by the adverse effect of elevated lactate in advanced stage HBV-related HCC patients. (C) 2018 Elsevier Masson SAS. All rights reserved.