Interleukin‐6 (IL‐6) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). Recently, it was reported in mouse models that estrogen‐mediated inhibition of IL‐6 production explains the gender disparity in HCC. We conducted a retrospective cohort study to examine whether this hypothesis is applicable to human HCC. We enrolled 330 patients with chronic hepatitis C whose serum samples were collected between January 1994 and December 2002. Serum IL‐6 concentrations were measured and patients were divided into three groups according to IL‐6 levels: low, middle, and high. We evaluated the association between serum IL‐6 levels and the risk of subsequent HCC development, including subgroup analysis on each gender. During the follow‐up period (mean 9.0 yr), HCC developed in 126 patients. The incidence rates differed significantly among the three groups (p = 0.015), increasing in accordance with serum IL‐6 levels. However, unexpectedly, this tendency was significant only in female patients. In a multivariate analysis, higher serum IL‐6 level was an independent risk factor for HCC development in female patients, with a hazard ratio of 1.61. Although female patients showed a weak negative correlation between serum IL‐6 levels and estradiol levels, the lower risk of HCC in female patients cannot be fully explained by estrogen‐mediated inhibition of IL‐6 production. In conclusion, higher serum IL‐6 level was an independent risk factor for HCC development in female but not male chronic hepatitis C patients. Measurement of serum IL‐6 levels may provide useful information for predicting future HCC development in female chronic hepatitis C patients. © 2009 UICC