A hemorheological mechanism has been proposed for the hemodynamic effects of cyclosporin A (CsA). In vivo and in vitro effects of CsA on red blood cell (RBC) deformability were investigated in guinea pigs. RBC transit time, measured by a cell transit analyzer, was found to be prolonged, implying impaired deformability in guinea pigs treated with CsA (10 mg/kg/day) for 7 days. Blood CsA concentration was approximately 900 ng/ml. RBC cytosolic calcium concentration was higher in the CsA-treated groups than in the control group. RBC lipid peroxidation was not affected. Combining pentoxifylline injections (100 mg/kg/day) with CsA therapy did not prevent the effect on RBC deformability and cytosolic calcium concentration. CsA did not affect RBC transit time and cytosolic calcium concentration in vitro. Thus, the influence of CsA on RBC deformability appears to be an indirect effect that is mediated by the alterations in RBC calcium homeostasis.