In chronic hepatitis C virus (HCV) infections, the current standard of care (combination therapy with pegylated alpha interferon (PEG-IFNα) and ribavirin) is only effective in around 50% of cases. The aim of the present study was to analyze the relationship between the HCV load and the PEG-IFN concentration during the first week of treatment. Fifteen treatment-naive patients with chronic hepatitis C infection (genotypes 1, 2, 3, and 4) underwent PEG-IFNα-2b/ribavirin combination therapy. Blood samples were collected before the first injection (T0) and then at different time points until the next injection a week later. The PEG-IFN concentration and the HCV load were assayed. The serum interferon concentration peaked 2 days after the first injection (mean value for the study population; Tmax = 40.9 hr; Cmax = 490 pg/ml) and a trough in viral load was seen at day 3. The PEG-IFNα-2b concentration decreased from day 2 to day 7, enabling a viral rebound in all patients. The change in viral load between day 0 and day 3 differed significantly according to whether the patients were responders at week 12 (Δlog d0/d3 = 2.729 ± 1.419 log10 IU/ml) or not (Δlog d0/d3 = 1.102 ± 0.472 log10 IU/ml). Our results emphasize the potential clinical importance of achieving viral decay immediately after initiation of interferon–ribavirin combination therapy. J. Med. Virol. 82:1640–1646, 2010. 2010 Wiley-Liss, Inc.