Summary. Standard of care for patients with chronic hepatitis C is pegylated interferon (pegIFN) combined with ribavirin (Rbv). It results in persistent viral eradication and prevents the progression of liver disease and the associated complications in about 50% of treated patients. Currently, two PegIFNs are available that differ significantly in terms of pharmacokinetic and pharmacodynamic profiles as a consequence of different pegylation chemistries. While the registration trials of the two therapeutic regimens demonstrated the superiority of each PegIFN vs the native IFN α2b, the superiority of one regimen over the other in terms of treatment efficacy remains unknown. Retrospective cohort studies and randomized prospective head-to-head trials have attempted to resolve the considerable controversy over this issue and support evidence-based treatment decisions.