Background Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEG-IFN)-α and ribavirin for chronic HCV remain low (∼10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. Methods We randomized 30 HCV genotype 1 ( n=24) and genotype 4 ( n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed® 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000–1,600 mg) for 48 weeks. Results The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively ( P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The perprotocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. Conclusions Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent.