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CD4 and CD8 antigen coexpression occurs not only on blastic T-cell malignancies, but also on a small subset of mature lymphocytes. The aim of this study was to determine the prevalence of this population of cells and to identify features that can be used to differentiate them from T lymphoblasts.All specimens submitted to the clinical flow cytometry laboratory from August 1, 1994, through July 31, 1995, were analyzed for CD4 and CD8 coexpression.Percentage of lymphocytes coexpressing the CD4 and CD8 antigens.Four percent (22/526) of all specimens contained a population of CD4/CD8 coexpressing cells. Five cases represented CD4 and CD8 antigen expression on neoplastic cells. In 17 cases, the CD4/CD8 coexpressing cells appeared to represent a population of mature lymphocytes with a normal phenotype. The immature cells of T-cell acute lymphocytic leukemia and lymphoblastic lymphoma represented a dominant uniform population of cells demonstrating strong staining with both the CD4 and CD8 antigens. Cases containing a mature population of CD4/CD8 coexpressing cells were characterized by fewer coexpressing cells and variable expression of CD8. There were cases where distinction of this population of mature CD4/CD8 coexpressing lymphoid cells from a blastic malignancy was not possible using immunophenotyping alone.Correlation of clinical, morphologic, and immunophenotypic data is recommended to prevent the misdiagnosis of subtle involvement by a blastic T-cell malignancy.