To determine whether specific T-cell activation pathways could produce nuclear contour irregularity in normal human lymphocytes, purified T cells were stimulated in vitro and subsequently analyzed by electron microscopy. The degree of nuclear contour irregularity was determined with the use of a computerized planimeter. Stimulation via the T-cell receptor (TCR)/CD3 complex using anti-CD3 monoclonal antibodies induced Sézary-like morphology (nuclear contour indices > 6.5) in a significant portion (9% to 28%) of T cells derived from different normal donors. T-cell activation via CD2 antigens showed induction of Sézary-like nuclear morphology in a lower percentage of cells in comparison with stimulation via the TCR/CD3 complex. In contrast, mitogenic stimulation in vitro did not induce alterations of nuclear morphology in T cells. Immunoelectron microscopy showed that nuclear contour irregularity induced in vitro did not correlate with surface-antigen expression of T-cell subpopulations. The results indicate that Sézary-like morphology is associated with cell activation in normal human T cells.