In the absence of antiviral treatment, chronic hepatitis C virus (HCV) infection is a liver disease characterized by the development of necroinflammatory changes and progressive liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The approval of ribavirin in combination therapy regimens with interferon (IFN) dramatically improved therapy. Another advance was the introduction of pegylated IFNs, which allow a once-weekly subcutaneous administration and show more favorable pharmacokinetics and greater efficacy. Two forms are available: pegylated IFN alpha-2b (12 kDa) (1.5 microg/kg) and pegylated IFN alpha-2a (40 kDa) (fixed dosage of 180 microg). Ribavirin is administered orally, at doses > or =10.6 mg/kg, resulting in higher sustained virological responses (SVR) than IFN monotherapy. The highest SVR rates are attained with pegylated IFNs in combination with ribavirin. Factors associated with treatment outcome include HCV genotype, viral load, body weight, age, cirrhosis or bridging fibrosis, coinfection with HIV or hepatitis B virus, and treatment adherence and tolerance. Currently, the main therapeutic challenges ahead are: (a) the dosage optimization of pegylated IFNs and ribavirin according to the patients' characteristics; and (b) to evaluate the efficacy and safety of this combination therapy for difficult-to-treat patients, such as nonresponders, cirrhotics, transplant recipients, renal disease patients or those coinfected with HIV.