CD4+ T and regulatory T cells (Tregs) seem to play a key role in persistence of hepatitis B virus (HBV) infection. However, the molecular events by which Tregs exert their modulatory activity are largely unknown. The transcriptional profiles of CD4+ T cells of healthy controls (HCs) and patients affected by acute hepatitis B (AVH-B) or chronic hepatitis B (CHB) infection were established using a custom expression array consisting of 350 genes relevant for CD4+ T cell and Treg function. These studies were complemented by real-time reverse-transcription polymerase chain reaction. Peripheral blood mononuclear cells (PBMCs) were also analyzed for the presence of Tregs, which were more abundant in the acute stage of the disease (7%) than in HCs and CHB infection (HCs versus AVH-B, P = 0.003; AVH-B versus CHB, P = 0.04). One hundred eighteen genes (34%) intrinsically differentiate HBV-infected patients from HCs. Using gene ontology, we identified T cell receptor signaling and clusterization, mitogen-activated protein kinase kinase signaling, cell adhesion, cytokines and inflammatory responses, cell cycle/cell proliferation, and apoptosis as the most prominent affected modules. A higher expression of CCR1, CCR3, CCR4, CCR5, and CCR8 was seen in AVH-B than in CHB-infected patients and HCs. Annotation of the interconnected functional network of genes provided a unique representation of global immune activation during acute infection. Almost all genes were down-regulated in patients with CHB infection. Conclusion: The fingerprints enable clear discrimination between patients suffering from AVH-B or CHB infection. The observed profiles suggest accumulation of effector T cells with a potential role in necro-inflammation during the acute stage. Subsequent down-regulated effector functions support the hypothesis of suppressed CD4+ effector T cells favoring viral persistence in the chronic infection stage. (HEPATOLOGY 2009.)