Summary.  The relationship between the balance of helper T‐cell type 1 (Th1) or type 2 (Th2) cytokines and the clinical course of hepatitis C virus (HCV) infection is unclear. We evaluated Th1 [interleukin (IL)‐2, interferon‐gamma (IFN‐γ)] and Th2 cytokine (IL‐4, IL‐10) and 2,5‐oligoadenylate synthetase (OAS, an IFN‐induced antiviral protein) production by peripheral blood mononuclear cells from 10 healthy anti‐HCV‐positive individuals (group A), 10 HCV‐RNA‐positive with persistently normal alanine aminotransferase (ALT) levels (group B), 10 HCV‐RNA‐positive with abnormal ALT (group C) and 10 uninfected healthy controls. IL‐2 production was significantly increased in group B when compared with all the other groups. No difference was found for IFN‐γ. IL‐4 was significantly higher in group C than in both group B (P = 0.0006) and controls (P = 0.004). Compared with controls, IL‐10 was significantly decreased in group A (P = 0.013) and B (P = 0.004). The production of 2,5‐OAS was significantly higher in group B than in A (P = 0.04) and in C (P = 0.004). Finally, in all HCV‐RNA‐positive patients, a significant correlation was found between ALT and both IL‐2 (r = −0.78; P = 0.0008) and IL‐4 (r = 0.75; P = 0.0008). In conclusion: (i) subjects who cleared HCV showed a cytokine profile similar to controls; (ii) a preferential shift towards a Th1 profile seems associated with a more favourable clinical outcome in chronic hepatitis C; and (iii) a prevalent Th2 profile seems implicated in HCV pathogenesis and severity of liver disease.