Chronic infection with HCV has an estimated prevalence of 1.6-2.0% worldwide and is a major cause of liver-related death. The first attempts to halt the progression of infection relied on the empirical use of interferon (IFN), a naturally occurring cytokine that is implicated in antiviral innate immunity. The first studies of this treatment in the early 1990s, however, led to disappointing response rates. These response rates subsequently improved with the empirical addition of the guanosine analog ribavirin to the treatment regimen. To improve the effectiveness and tolerability of the three times per week therapeutic schedule of IFN, two forms of pegylated interferon (PEG-IFN) were developed in the early 2000s-PEG-IFN-alpha2a and PEG-IFN-alpha2b. These two compounds differ markedly in size, structure, site of attachment of the polyethylene glycol moiety and type of bond involved in pegylation, which ultimately confer different pharmacokinetics and biological activity. Unsurprisingly, researchers question whether the two PEG-IFNs also differ in clinical effectiveness, but the re-analysis of restrospective studies and the results of three head-to-head studies have left this issue open. We have, therefore, scrutinized the design and conduct of all available studies to unravel the reasons behind the therapeutic differences between PEG-IFN-alpha2a and PEG-IFN-alpha2b.