Summary. Interferon-α (IFN-α) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK–STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN-α is demonstrated here. The transcriptional levels of SOCS-1 and -3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription-polymerase chain reaction. We established stable transfectants of SOCS-1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS-1 on the phosphorylation of IFN-α-induced STAT-1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS-1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS-1, but not SOCS-3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN-α-induced STAT-1 phosphorylation and the expression of antiviral genes were inhibited in SOCS-1-transfected cells. Patients showing high SOCS-1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS-1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS-1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS-1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.