A serum or plasma factor in certain patients with focal segmental glomerulosclerosis (FSGS) has been found to increase glomerular albumin permeability (P(alb)) and causes proteinuria in experimental animals. High P(alb) is associated with recurrence of FSGS after transplantation, but serial studies of P(alb) activity in patients with native kidney FSGS have not been performed, and the relationship between P(alb) and remission of proteinuria is not known. This study was designed to determine P(alb) activity before, during, and after 24 wk of treatment with cyclosporine or placebo given as part of a randomized controlled trial in steroid-resistant FSGS patients with nephrotic range proteinuria. Pretreatment P(alb) averaged 0.36 +/- 0.22 and was not significantly different between treatment groups and was not altered during or after the test medication. There was no association between P(alb) activity and remission or relapse in proteinuria. The average P(alb) activity in native kidney FSGS was lower than in previously reported patients with posttransplant recurrence of the disease, and its level did not vary during the course of the study. The antiproteinuric effect of cyclosporine appeared independent of changes in P(alb). This finding is consistent with a direct effect of cyclosporine on glomerular barrier function and/or that within this group of patients the variations in proteinuria are not reflected in changes in Palb because of its limits in terms of reproducibility and responsiveness.