Although several virus- and host-related predictive factors for the response to interferon alfa (IFN-α) have been defined in patients with chronic hepatitis C, no pretreatment parameter can definitely predict the response to antiviral treatment. Assessment of the initial response by quantification of serum hepatitis C virus RNA before and 4 weeks after initiation of therapy may be a clinically applicable and reliable parameter to predict long-term response. Therefore, the aims of the present study were to test the predictive value of a decline in HCV RNA of at least 3 log in the first 4 weeks of treatment (▵HCV RNA) in patients treated with 3 × 106 units of recombinant IFN-α2a (rIFN-α2a) three times per week subcutaneously and to compare ▵HCV RNA with other established predictive factors, such as HCV genotype and pretreatment viremia. Serum HCV RNA was measured by a validated quantitative reverse transcription–polymerase chain reaction (RT-PCR). Geno/subtyping of HCV was performed by direct sequencing of the nonstructural (NS) 5B region of PCR-amplified isolates and subsequent phylogenetic analysis. Stable HCV RNA levels (▵HCV RNA ≤ 1 log) within the first 4 weeks of IFN-α treatment were present in 42 of 70 patients. A decline in HCV RNA levels between 1 to 3 log and more than 3 log was observed in 9 (13%) and 19 patients (27%), respectively. In 21 of 70 patients (30%), HCV RNA was not detectable at the end of 12 months' treatment. Three of 26 patients (11%) with a pretreatment viremia of ≤106 copies/mL (all HCV subtype 3a) and 6 of 44 patients (14%) with a pretreatment viremia of >106 copies/mL (HCV subtypes 1b, 2a, 2c, 3a [two patients], and 4) achieved a virological sustained response to interferon-α2a treatment. All patients with a virological sustained response had an initial ▵HCV RNA of more than 3 log. In a stepwise discriminant-function analysis, the initial ▵HCV RNA was confirmed as the strongest predictor of virological sustained response (P < .0001). In conclusion, the data of the present study suggest that IFN-α treatment can be terminated after 4 weeks in patients with a decrease in HCV RNA levels of less than 3 log, when apparent HCV eradication is considered the therapeutic target. The predictive value of ▵HCV RNA clearly exceeds the significance of HCV genotype and pretreatment viremia as predictors of successful IFN-α treatment.