<i>Objective:</i> To investigate whether interleukin-6 (IL-6) polymorphisms could be associated with the occurrence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and whether this influence could act synergistically with the gender of the patient. <i>Methods:</i> We studied 219 consecutive patients who underwent liver transplantation for liver cirrhosis. All total hepatectomy specimens were sectioned at intervals of 1 cm in search for suspicious focal hepatic lesions. Genotyping for the IL-6 –1363 G>T, –597 G>A, –572 G>C, –174 G>C and +2954 G>C polymorphisms was performed by restriction fragment length polymorphism. <i>Results:</i> A significant association was found between the presence of the A-C/A-C low producer diplotype (–597 G>A/–174 G>C loci) and absence of HCC (18/153 vs. 1/66, p < 0.02). With respect to the IL-6 A-C/A-C low producer phenotype (n = 19), females (n = 60) and males (n = 140) with the high producer phenotypes had an adjusted odds ratio for the presence of HCC of 3.74 and 14.8, respectively (p < 0.001). <i>Conclusions:</i> Polymorphisms of IL-6, by determining differences in its expression, are associated with HCC occurrence among patients with liver cirrhosis. The protective effect of female gender against the occurrence of HCC occurs mainly among carriers of IL-6 high producer phenotypes.