Cyclosporine (CsA) is a potent immunosuppressive compound, and its metabolites have previously been shown to have pharmacologic activity. The aldehydic metabolites have been isolated and are a metabolic intermediate after the conversion of CsA to its most active hydroxylated metabolite. The in vitro sensitivity of alloreactive T-lymphocytes, which are generated from a mixed lymphocyte reaction and propagated from organ transplant biopsy specimens to the aldehydic metabolites of CsA, was tested. In secondary proliferative assays in the presence of varying concentrations of CsA and the aldehydes, the concentration required to inhibit proliferation by 50% was 50 to 150 ng/mL for CsA and 3150 to 3500 ng/mL for the aldehydes. Pretreatment of alloreactive cells with CsA or the aldehydes did not alter cell viability, as tested with dye exclusion, or cell reactivity on reculturing. These studies concluded that the structural modification formed by metabolism of CsA to the aldehydic structure eliminates its antiproliferative activity on T-lymphocytes.