Abstract Background: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC. Methods: We conducted a nested case–control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI). Results: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12–2.11; OR = 4.88 (1.46–16.3); OR = 3.79 (1.10–13.0); OR = 4.13 (1.13–15.1) with each additional quintiles, respectively] with a significant dose–response trend (Ptrend = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62–4.39); OR = 3.85 (1.47–10.1); OR = 2.56 (0.96–6.84); OR = 3.76 (1.33–10.7) for the second, third, fourth, and fifth quintiles, respectively; Ptrend = 0.017] before HCC. Conclusions: Elevated adiponectin levels were independently associated with an increased risk of HCC. Impact: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown. Cancer Epidemiol Biomarkers Prev; 23(8); 1659–71. ©2014 AACR.