The ζ-chain is a unique component of the T cell receptor (TCR) with no sequence homology to other CD3 molecules. The ζ-chain acts to stabilize the TCR on the cell surface and to transmit signals to different transduction pathways in the cell. T cells from patients with autoimmune diseases, with chronic inflammation, and suffering malignant tumors are functionally impaired in that they express decreased ζ-chain. Acquired aplastic anemia (AA) is a bone marrow failure syndrome characterized by T-cell immune mediated destruction of hematopoietic stem cells. Oligoclonal expansion of T cells correlates with disease activity. In this study, we examined TCR ζ-chain protein levels in aplastic anemia patients. Twelve out of sixteen patients (75%) examined displayed decreased ζ-chain protein levels compared to normal controls (p=0.008). As a control, no differences were detected in expression of the TCR ε-chain. Patients and healthy donors displayed comparable amounts of Zap-70, the kinase responsible for full phosphorylation and activation of the ζ-chain. There was no correlation with disease status or medical treatment at the time of sampling. Four patients were re-examined for ζ-chain protein levels at 3 month intervals, but there was no change in their ζ-chain expression pattern despite hematologic improvement. We hypothesized correlation between ζ-chain and IFN-g levels in T cells from patients with AA. When we estimated IFN-g levels by flow cytometry, all 5 patients examined had increased IFN-g levels, of whom 4 had decreased ζ-chain levels: intracellular IFN-g was reciprocally correlated with ζ-chain protein levels. In summary, our data indicate that TCR ζ-chain expression is decreased in the majority of patients with AA, regardless of disease activity or treatment status. ζ-chain-deficient T cells from AA patients also overproduce IFN-g. Is ζ-chain down-regulation the primary event leading to IFN-g over-production, or is IFN-g responsible for the ζ-chain down-regulation? One possible explanation is an intrinsic defect in the TCR leading to alterations in kinases and transcription factors downstream of the ζ-chain-Zap-70 association. Whether ζ-chain expression correlates with expanded Vb clones observed is to be established. The seqeunce of molecular events described in the current work may lead to the Th1 shift observed in aplastic anemia, but further studies are needed to explore the possible role of ζ-chain downregulation to the pathogenesis of AA.