Abstract Background: Excess body weight is an independent risk factor for primary liver cancer, and the role of adiponectin in the pathogenesis of obesity-related malignancies is a focus of research interest. Few prospective studies have examined the association between circulating adiponectin and liver cancer risk, so we investigated this association in a nested case–control study of a population-based prospective cohort in Japan. Methods: From 18,628 target participants of ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or C virus infection at baseline (n = 1,544). Among these, 90 were newly diagnosed with primary liver cancer from 1993 through 2006, and matched to 177 controls. The ORs of liver cancer development based on plasma levels of adiponectin were estimated with a conditional logistic regression model. Results: Median values of total and high-molecular-weight (HMW) adiponectin tended to be higher in the patients with liver cancer, and plasma levels of adiponectin were positively associated with liver cancer risk. Body mass index– and diabetes-adjusted ORs for the highest tertile of total and HMW adiponectin levels versus the lowest were 3.30 [95% confidence interval (CI), 1.45–7.53; Ptrend < 0.01] and 3.41 (95% CI, 1.50–7.73; Ptrend < 0.01), respectively. There was no effect modification by body mass index and diabetes. Conclusions: Higher plasma adiponectin levels were associated with an increased risk of primary liver cancer in middle-aged Japanese adults with hepatitis virus infection. Impact: Circulating adiponectin levels may be a risk marker for primary liver cancer. Cancer Epidemiol Biomarkers Prev; 22(12); 2250–7. ©2013 AACR.