Hepatocellular carcinoma (HCC) is a frequent malignancy with a high rate of mortality, and the hepatitis B and C viruses are considered major etiological factors associated with the development of chronic inflammation. Today, there is increasing evidence that the inflammatory process, mediated by the complex cytokine network, is inherently associated with many cancer types, including HCC. In this study we have assayed Th1 cytokines, such as IL-18 and IFN gamma, in the sera of 23 HCC patients with HCV infection, analysing their possible association with HCC in respect to 20 patients: 12 carriers for HCV infection and 8 healthy controls. We have also evaluated the possible difference on IL-18 and IFN gamma in HCC patients with respect to the number of hepatic nodules and rate of tumor differentiation. The mean values of serum IL-18 levels were significantly higher in HCC patients than in HCV carriers (p < 0.001) while IFN gamma serum levels were similar in cases and controls. No significant correlation was present between IL-18 and IFN gamma. In addition, IL-18 was higher in HCC patients with two or more nodules in respect to HCC patients with one nodule (372+/-140 vs 109+/-73 pg /mL; p <0.001). There is no significant difference in HCC patients and no correlation between the cytokines and other evaluated variables such as HCV RNA, alpha-1 fetoprotein, genotype and demographics of HCC patients. Taken together, our data suggest that IL-18 may play a key role in the pathogenesis of HCC and its levels can be utilized as a possible marker in the diagnosis of HCC.