In long-term renal allograft recipients on conventional immunosuppression, we have previously reported an abnormal expansion of CD3+/Leu-7+cells. These cells are large granular lymphocytes without any natural killer activity. About 20% of these CD3+/Leu-7+cells coexpress the CD4 differentiation antigen. In 65 transplant recipients at risk for more than 6 months, the mean percentage of peripheral blood CD4+/Leu-7+cells is significantly increased compared with 34 normals (5.0±0.6% versus 1.0±0.1%, P<0.0001). Patients who never received azathioprine do not show such an abnormality. We carried out this study to further define the phenotype, morphology, and function of these cells. As to phenotype, they coexpress CD2, CD3 but do not coexpress CD1, CD8, CD11, CD16, CD19, CD25, HLA-DR, Leu-M3. Morphologically, CD4+/Leu-7+cells are typical large granular lymphocytes undistinguishable from CD 16+effector NK cells. CD4+/Leu-7+cells do not exhibit any natural killer cell activity. In contrast to CD4+/ Leu-7-cells, CD4+/Leu-7+cells do not proliferate when stimulated with either lectins (Con A, PHA) or allogeneic cells. When stimulated for 3 days with PHA, sorted CD4+/Leu-7+cells do not express IL-2 receptors as detected with a PE-conjugated anti-CD25 monoclonal antibody, whereas 40% of CD4+-Leu-7-cells do so. Finally, when stimulated with PHA, CD4+-Leu-7+cells are not able to produce detectable levels of IL-2, while CD4+-Leu-7-cells do so. In long-term renal allograft recipients on conventional immunosuppression, Leu-7 antigen identifies a subset of CD4+cells that do not behave like regular T helper cells. We speculate that these cells represent an alteration in the cellular environment in transplant recipients, perhaps leading to long-term complications such as cancers and chronic viral infections.