Evidence suggests a link between adiponectin, an adipocytokine, and liver tumorigenesis. Different multimer complexes of adiponectin, with low-molecular weight (LMW), middle-molecular weight (MMW) and high-molecular weight (HMW), may have different roles. Therefore the present study was performed with the aim of assessing associations between these multimers and liver cancer development. A nested case-control study (59 liver cancer cases [mean age=63.5 years] and 334 controls [62.7 years]) was conducted as a part of the Japan Collaborative Cohort (JACC) Study recruiting healthy participants, aged 40-79 years, for the follow-up period from 1988-1990 to 1999. The end point was liver cancer occurrence/death. Serum levels of HMW, MMW and LMW adiponectin were determined at baseline using an ELISA assay. Multivariate-adjusted logistic regression analyses comparing the tertile levels of adiponectin multimers showed that the groups stratified with the highest percentage of LMW tended to have lower odds ratios (ORs) than the lowest group (OR adjusted for sex, age and area=0.54 [95%CI: 0.26-1.11] and adjusted for sex, age, area, body mass index, smoking, alcohol, coffee consumption, diabetes history and HCV-antibody positivity =0.50 [95%CI: 0.22-1.15]), albeit without statistical significance (set at p<0.05). Higher percentages of circulating LMW adiponectin may lead to a reduction of liver cancer risk and relationships with multimer composition may merit further study.