The serum concentration of hepatitis C virus (HCV) RNA is usually stable (4 to 8 log 10 IU/ml) in untreated patients with chronic hepatitis C. While this baseline HCV RNA concentration ([HCV RNA] BL ) is predictive of a sustained virologic response to treatment, its determinants are only partially identified. We therefore analyzed the baseline characteristics of 2,472 HCV genotype 1-infected patients to identify correlations with gender, age, race, weight, body mass index (BMI), HCV acquisition mode, HCV subtype, alanine aminotransferase concentration, or histopathologic changes in the liver. After separation of the data according to four [HCV RNA] BL groups (<5.0, >5.0 to 5.6, >5.6 to 5.9, and >5.9 log 10 IU/ml), we determined that increasing The serum levels of hepatitis C virus (HCV) RNA represent the abundance of HCV production versus clearance and are usually stable in humans with untreated chronic hepatitis C (CHC) (1,9,12,18,22,34,39,44,49,63). Between individuals, however, these baseline HCV RNA concentrations ([HCV RNA] BL ) vary by 3 to 4 log 10 IU/ml and the factors that determine these differences are poorly understood.To identify the determinants of interpersonal [HCV RNA] variability, one study examined [HCV RNA] among 969 individuals who acquired HCV through injection drug use (63). Human immunodeficiency virus type 1 (HIV-1)-coinfected individuals had higher [HCV RNA] than those who were infected only with HCV; and among the latter group, a lower [HCV RNA] was independently associated with younger age, ongoing hepatitis B virus infection, and the absence of needle sharing. However, these factors explained only 8.5% of the person-to-person variability in [HCV RNA]. Similar results were observed in cohorts of 676 female injection drug users and 313 current and former drug users (59, 65). These results may have been affected by HIV-1 coinfection, HCV reinfection, the biologic and analytic effects from the various HCV genotypes that infected these individuals, interassay variability of the assays used to quantify HCV RNA, or the absence of data for certain key factors or for very low [HCV RNA] (21,59,63,65).In studies of alpha interferon-based therapy for CHC, [HCV RNA] BL have been predictive of a sustained virologic response (SVR) (16,20,24,29,36,37,41,51,72). Another viral characteristic, the HCV genotype, has also been predictive of an SVR: genotype 1 (gt1), the most prevalent HCV type in the United States, was independently associated with a lower likelihood of achieving an SVR (9,15,16,24,37,72). Subsequently, patients with Ͼ2 ϫ 10 6 copies/ml of HCV gt1 RNA, which corresponds to 5.9 log 10 IU/ml, have been regarded to be less likely to achieve an SVR than those with lower baseline concentrations of HCV gt1 RNA or those with Ͼ5.9 log 10 IU/ml of gt2 or gt3 (16, 20, 24, 29, 36, 37, 41, 46-48, 51, 54, 72). We recently identified 5.6 log 10 IU/ml as the [HCV RNA] BL that best discriminated a high (70%) from a low (43%) SVR for 568 gt1-infected patients who were treated for 48 weeks with 180 g/week...