Cyclosporin A (CsA) may exert its cytotoxic effects by altering the activity of different plasma membrane transport systems. Although CsA may act at the gene level, it has been also suggested that it can directly alter transport processes at the plasma membrane. To examine this possibility in a physiological context, we determined Na(+)/K(+)-ATPase activity in erythrocytes from two groups of subjects receiving CsA treatment: group I consisted of kidney transplant patients, and group II comprised patients with steroid-resistant idiopathic nephrotic syndrome. Group I patients showed a marked decrease (35%) in the activity of the Na(+)/K(+)-ATPase in erythrocytes immediately after surgery, before the initiation of CsA treatment. The activity remained low 2 days after the introduction of CsA, but had recovered to the original (pre-surgery) value 1 month later. Group II patients showed the same pattern of erythrocyte Na(+)/K(+)-ATPase activity as those in group I. When the blood CsA levels from all patients were plotted against the corresponding erythrocyte Na(+)/K(+)-ATPase transport activity, a significant linear correlation was found. Higher levels of CsA in the blood were correlated significantly with increased Na(+)/K(+)-ATPase activities. The blood sodium concentration was also correlated positively with both erythrocyte Na(+)/K(+)-ATPase activity and blood CsA concentration. Thus CsA treatment is not associated with inhibition of the Na(+)/K(+)-ATPase in erythrocytes.