CD4+ CD8+ cells are present during T cell differentiation in the thymus. Less than 2% of normal T cells that coexpress CD4 and CD8 also are released in the circulation and are present in the peripheral blood. In this study, nine individuals are described that manifested persistent expansions (11% to 43%) of circulating CD4+ CD8+ T cells that in three cases had large granular lymphocyte (LGL) morphology in the absence of either lymphocytosis or overt lymphoproliferative disorders. Southern blot hybridization of enriched CD4+ CD8+ cells with T-cell receptor beta (TCR beta) and TCR gamma probes showed that most cases had the 12-kb Eco RI germinal band deleted or of decreased intensity. In several individuals new TCR beta-specific bands of different intensity and distinct from case to case suggested either monoclonal or oligoclonal and polyclonal expansions. Immunophenotypic analysis showed that in 7 out of 9 cases the CD4+ CD8+ T cells presented with CD8 dim expression. Furthermore, all the CD4+ CD8+ cells did not express many of the known activation antigens (low or absent CD25, CD38, CD71, HLA-DR), whereas they expressed high levels of CD2, CD29, CD56, and CD57. In addition, the CD4+ CD8+ cells of 5 out of 9 subjects coexpressed CD45RA and CD45RO suggesting that these cells might be "frozen" in an intermediate state between naive and memory T cells. In conclusion, the present CD4+ CD8+ cases fall within a larger spectrum of disorders ranging from apparently normal to reactive or proliferative situations and encompassing cells with LGL morphology or LGL-associated antigens expression either in the presence or in the absence of absolute lymphocytosis that deserve careful follow-up investigations.