Pending the emergence and approval of an effective interferon-free regimen, pegylated interferon will remain an integral part of the treatment of genotype 4 hepatitis C virus (HCV). A new 20 kDa pegylated interferon has been developed in a cost-saving fungal-based system and is commercialized in Egypt at a quarter to a third of the price of conventional pegylated interferon. We hereby test the efficacy and safety of this novel cost-saving interferon. One hundred ninety-three consecutive treatment-naive patients with genotype 4 HCV were treated using the following regimen: subcutaneous 20 kDa pegylated interferon 160 μg once weekly plus oral ribavirin 1,000 or 1,200 mg daily (based on body weight <75 kg or ≥75 kg, respectively) for 48 weeks. A sustained virological response (SVR) of 51% was achieved. Interim responses included rapid virological response (RVR): 54%, early virological response (EVR): 78% (complete EVR: 71%, partial EVR: 7%), and end of treatment response: 63%. The most common adverse events were flu-like symptoms, dyspepsia, anorexia, and pruritus. Treatment-related serious adverse events were encountered in only 2 patients (1%). Discontinuation of treatment due to adverse events occurred in only 13 patients (7%). Multiple logistic regression analyses revealed the following factors as predictors of SVR: RVR (P<0.001), alpha-fetoprotein<upper limit of normal (ULN) (P=0.007), and early biochemical response (alanine aminotransferase <ULN at week 12, P=0.018). Hansenula-derived 20 kDa pegylated interferon alpha-2a is an effective and safe treatment for genotype 4 chronic HCV. These results highlight the presence of a less costly treatment for chronic HCV, pending the emergence of an effective inexpensive interferon-free regimen. A direct comparison with 40 kDa interferon remains essential to adequately compare the efficacy and safety.