The attachment of a polyethylene glycol (PEG) polymer to a protein or peptide is becoming increasingly common within the pharmaceutical industry as a way of altering the activity of the parent molecule. Significant improvements in biological activity with PEG molecules have been seen with several licensed drugs, allowing for product life cycle management, as well as with experimental compounds in development that have pharmaceutical properties making them suitable candidates for pegylation. Among the various disease states that have been targeted for the study of drugs incorporating pegylation technology, the treatment of chronic hepatitis C with interferon-based compounds offers significant potential for clinical impact. Two separate compounds, peginterferon alfa-2a (PEGASYS) and peginterferon alfa-2b (PEG-Intron) are now both approved for use alone and in combination with ribavirin for the treatment of chronic hepatitis C. However, the different PEG moieties attached to the native protein, the site of attachment and the type of bond involved lead to vast differences with respect to the pharmacokinetics (including absorption, biodistribution, metabolism and elimination) and pharmacodynamics of these two compounds. This article discusses the differences that exist between these compounds, which may lead to different clinical profiles for their use in the treatment of patients with hepatitis C.