Hepatocellular carcinoma (HCC) has been associated to diabetes and obesity, but a possible association with the metabolic syndrome (MetS) and its potential interaction with hepatitis is open to discussion. We analysed data from an Italian case-control study, including 185 HCC cases and 404 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from unconditional logistic regression models. Among the MetS components, diabetes and obesity (i.e, body mass index (BMI)≥30 kg m(-2)) were positively associated to HCC risk, with ORs of 4.33 (95% CI, 1.89-9.86) and 1.97 (95% CI, 1.03-3.79), respectively. The ORs for the MetS were 4.06 (95% CI, 1.33-12.38) defining obesity as BMI≥25, and 1.92 (95% CI, 0.38-9.76) defining it as BMI≥30. The risk increased with the number of MetS components, up to an almost four-fold excess risk among subjects with ≥2 MetS factors. Among subjects without chronic infection with hepatitis B and/or C, the OR for those with ≥2 MetS components was over six-fold elevated. There was no consistent association in subjects with serological evidence of hepatitis B and/or C infection. This study found that the risk of HCC increases with the number of MetS components in subjects not chronically infected with hepatitis viruses.