Abstract: Objective During hepatitis B virus-related cirrhosis patients with nucleos (t) ide analogues (NUCs) treatment, to investigate the relationship between hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) mutations and patient initial taking NUCs. Methods The clinical data of 79 patients with baseline for HBV related liver cirrhosis, who experienced poor efficacy or virological breakthrough during NUCs treatment and genotyped by pyroscquencing for 9 mutation sites in the HBV P gene that have been previously correlated to NUC efficacy, were analyzed, retrospectively. Analysis of patients with previous drug use, drug-resistant mutation patterns. According to HCC occurred, we divided 79 patients into two groups to compare the differences in cirrhosis at baseline levels (compensated/decompensated), baseline HBV DNA, baseline alanine aminotransferase (ALT), baseline aspartate aminotransferase (AST), sex, age, HBsAg, HBeAg and resistance mutation patterns and other aspects of comparison, respectively. According to previous initial application LAM or ADV, patients were divided into two groups to compare the differences in HCC patients and virus mutation patterns, respectively. Results HCC patients were found in 12.66% (10/79) of the 79 patients. The average age of HCC group was older than that of liver cirrhosis (LC) group [(58.30 ± 6.40) years old vs. (51.64 ± 7.69) years old; t = 2.609, P = 0.011]. The serum AFP level at HCC group was higher than that at LC group [(566.24 ± 563.79) ng/ml vs. (17.32 ± 77.04) ng/ml; t = －7.879, P = 0.000]. The presence of rtA181T mutation and age ＞ 50 years occurred more frequently in HCC group (70.0%, 100.0%) than those in LC group (24.6%, 52.2%) (χ2 = 6.488, P = 0.011; χ2 = 6.365, P = 0.012), respectively. The initial taking ADV or LAM patients were found in 48.10% (38/79) or 45.57% (36/79) of the 79 patients, respectively. HCC occurred more frequently in the initial taking ADV group (23.7%) than that in the initial taking LAM group (2.8%) (χ2 = 5.240, P = 0.022). Conclusions During HBV-related cirrhosis patients with NUCs treatment, emergence of the rtA181T mutant might be associated with occurrence of HCC. HBV-related cirrhosis patients who are older than 50 years old and initial taking ADV poor efficacy or virologic breakthrough occurs, needed to detect HBV P gene mutation and close follow-up of HCC development in the subsequent courses of antiviral therapy. An initial dose of ADV-resistant mutation in patients with cirrhosis compared with an initial dose of LAM-resistant mutation may be more likely to progress to HCC.