Hepatitis C virus (HCV) is a leading public health problem affecting as many as 4 million Americans. Chronic HCV infection can progress to hepatocellular carcinoma, cirrhosis and death. Interferon-α-based therapies, initially as monotherapy and later in combination with ribavirin, have proven effective in the treatment of HCV infection, but standard interferon is hampered pharmacokinetically by a short half life. With the advent of the pegylated-interferons, administered in combination with oral ribavirin, the chances for HCV eradication have improved further. Peginterferon α-2b, the formuation discussed in this review, provides greater antiviral pressure while maintaining a tolerable side-effect profile with more convenient once-weekly dosing. Clinical trials have focused on treatment-naïve patients as well as on many different HCV subpopulations, including difficult-to-treat patients such as previous interferon therapy failures and patients with HCV cirrhosis.