OBJECTIVE Recent studies have reported a high prevalence of diabetes mellitus in populations infected with Virus C (HCV). The aim of this study is two-fold: a) to support the hypothesis of hyperinsulinemia as a risk factor for developing diabetes in these patients, with a prospective determination of baseline insulinemia in non-diabetic cirrhotic patients infected with HCV, comparing their values with those of a group of non-HCV non-diabetic cirrhotic patients; b) to investigate in both groups the factors associated to increased peripheral resistance to insulin. METHODS Thirty two HCV cirrhotic diabetic patients (group I) and 41 non-diabetic cirrhotic patients of other etiologies (group II) participated in the study. Baseline insulinemia, as well as factors related to insulin resistance such as age, anthropometric indexes, stage of cirrhosis development using the Child-Pugh index, serum ferritin and treatment with insulin resistance inducing drugs were compared in both groups. RESULTS Average baseline insulinemia in group I was 21.5 mU/ml (18.6-24.4), vs 14 mU/ml (10-18) in group II (p < 0.001), and the percentage of hyperinsulinemia was 87.5% (72.5-95.9) vs 56.1% (40.8-70.6), respectively (p < 0.01). No differences were observed between the two groups when comparing the following variables: age [54.4 (48.3-60.6) vs 59.9 (56.3-62.7) years of age, NS], weight [72.9 (69.5-76.3) vs 74.2 (70.8-77.7) kg, NS], height [163.6 (160.5-166.7) vs 161.3 (159.4-163.2)] cm, NS], body mass index [27.6 (26.1-29.1) vs 28.4 (27.3-29.5) kg/m2 of height, NS]; and Child-Pugh staging score (A: 31 vs 27; B: 0 vs 7; C: 1 vs 7, NS). However, serum ferritin levels in group I patients were higher than those in Group II [123.3 (12.4-289.3) vs 65.5 (2.4-306) ng/ml, p < 0.05]. It must be considered that at the recruitment 3 patients in Group I were taking either diuretics or non-selective beta-adrenergic blockers, compared to 14 patients in Group II, p < 0.01. Finally, the multivariate logistic regression analysis showed that insulinemia values (OR = 1.21; CI 95% 1.09-1.34, p < 0.001) and ferritin levels (OR = 1.21; CI 95% 1.02-2.69, p < 0.04) were independent variables associated to HCV infection. CONCLUSIONS HCV-positive non-diabetic cirrhotic patients have higher baseline insulinemia levels and increased prevalence of hyperinsulinemia than cirrhosis due to other etiologies. This could be explained by an increase of peripheral insulin resistance, mediated by the increase of iron deposits in these patients, and could be responsible for the increased risk of developing diabetes mellitus.