Cyclosporin A (CyA) is the immunosuppressive treatment of choice in preventing allograft rejection and graft-versus-host disease. However, clinical trials indicate that there may exist inter-individual variations in sensitivity to the drug. We have approached this issue by studying CyA-mediated inhibition of in vitro alloreactions, as measured by mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML), using mouse and human normal spleen cells. The differences between individuals in the CyA concentration required for 50% inhibition of the human alloreactions were twentyfold for the MLR and fortyfold for the CML. Moreover, the CML appeared to be inhibited at lower doses of the drug. No correlation was found between inhibitory doses and variables such as the magnitude of the response, age, or human leukocyte antigen phenotype. When the same experiments were performed with mouse spleen cells, no differences were observed among eight inbred strains. The lack of demonstrable individual sensitivity of mice in relation to humans is discussed.