Chronic evolution of acute hepatitis C (aHC) occurs in more than 80% of patients but can frequently be prevented by early treatment with interferon (IFN)-␣. Plasmacytoid dendritic cells (pDCs) are the major endogenous IFN-␣ producers, but their role in aHC is unknown. In this study, frequency, phenotype, and pDC function were analyzed in 13 patients with aHC and 32 patients with chronic hepatitis C (cHC) compared with 20 healthy controls, 33 sustained responders to antiviral treatment, 14 patients with acute hepatitis B (aHB), and 21 patients with nonviral inflammatory disease. In aHC, pDCs in the peripheral blood were significantly reduced compared with healthy controls (median, 0.1% vs. 0.36%, P < .0005) and were inversely correlated to alanine aminotransferase levels (r ؍ ؊0.823; P < .005). Circulating pDCs in aHC were immature, as determined via reduced expression of HLA-DR and CCR7, and produced little amounts of IFN-␣ (median, 3.5 pg/50,000 peripheral blood mononuclear cells [PBMCs] vs. 498.4 pg/50,000 PBMCs in healthy controls; P < .0005). Less pronounced changes were present in cHC (median, 0.17%, 28.0 pg/50,000 PBMCs IFN-␣, respectively). However, a significantly reduced frequency and IFN-␣ production was also found in self-limited aHB (median 0.1%, 8.6 pg/50,000 PBMCs) and in patients with nonviral inflammatory disease (median 0.19%, 7.5 pg/50,000 PBMCs). In conclusion, in aHC frequency and IFN-␣-producing capacity of peripheral blood pDCs are dramatically reduced and inversely correlated with the degree of liver inflammation. In cHC there is incomplete recovery of pDC function, which, however, could be solely due to the chronic inflammatory state. (HEPATOLOGY 2005;41:643-651.) H epatitis C virus (HCV) infection leads to chronic viral persistence in the majority of newly infected patients. Nevertheless, approximately 15% of all patients and up to 50% of symptomatic subjects with acute hepatitis C (aHC) spontaneously achieve long-term viral clearance, 1 which is attributed to a strong HCV-specific CD4 ϩ T helper 1 and CD8 ϩ cytotoxic T-cell response. [2][3][4][5] In contrast, once chronic HCV persistence is established, spontaneous viral clearance becomes extremely rare. 6 The acute and chronic phases of HCV infection also differ remarkably in their response to antiviral treatment: whereas in chronic hepatitis C (cHC), a combination treatment of pegylated interferon (IFN)-␣ and ribavirin is required to achieve approximately 50% of sustained virological response, 7,8 in aHC, monotherapy with conventional IFN-␣ leads to more than 95% sustained viral clearance. 9 The reasons for the difference in treatment response between aHC and cHC are currently not understood. Nevertheless, it seems that the substitution of IFN-␣ in the early phase of virus-host interaction during aHC successfully interferes with a process that is required for chronic viral persistence, suggesting that type I IFNs play a central role in the initial interaction between HCV and the host.