AbstractCyclosporin A (CsA) is used as a clinical immunosuppressive agent. Despite its immunosuppressive potential, some studies involvingin vivoadministration of cyclosporin have failed to verify the immunosuppressive activity of this agent. The present study investigates the effect of different concentrations of CsA addedin vitro, or of different doses of CsA administeredin vivo, on the ability of murine spleen cells to produce interleukin 2 and to generate cytotoxic T lymphocytesin vitrowhen stimulated with TNP‐self or H‐2 alloantigens. The results indicate that self Ia‐restricted T helper (Th) cells are more sensitive to lower doses of CsA than Thcells that are allorestricted. Thus, doses of CsA were found (15–30 mg/kg) that inactivated self Ia‐restricted Thfunction, but not other Thor effector function. This Thcell defect could be partially correctedin vitroby addition of Thcell factors to the sensitization cultures. A higher dose (75 mg/kg) of CsA inactivated all detectable T cell responses, and this defect was not corrected by addition of Thcell factors. T cell function returned to normal levels within two weeks of cessation of CsA at all three doses of CsA tested. The selective loss of L3T4 Thfunction at the lower doses of CsA was associated with a radiosensitive, Ly‐2 suppressor T cell that was selective in its action on self Ia‐restricted Thcell function. Loss of all T cell function at the higher dose of CsA was associated with a radioresistant non‐T suppressor cell that inactivated all T cell function tested. These results are discussed with respect to the selective dose‐dependent effects of CsA on Thsubsets, on the activation of suppressor cells with similar selectivity, and the implications of these findings on the use of CsA to prevent rejection of