The recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation has a potentially detrimental course toward the loss of renal function. To identify prognostic markers for recurrence and efficacy of treatment, we evaluated the outcome of 32 renal allografts in 29 pediatric patients with FSGS who underwent transplantation from 1987 to 1998 in the North Italy Transplant program. Recurrence was observed in 15 of 29 patients (52%) after the first transplant and in 3 of 3 patients (100%) after the second graft. No significant differences in sex, age at FSGS onset, age at transplantation, or length of dialysis were noted between patients with recurrent and nonrecurrent FSGS. Those with recurrence originally developed end-stage renal failure faster (3.9 years) than those without recurrence (6.2 years). Pretransplantation serum samples from 25 patients were tested in an in vitro assay that evaluates glomerular permeability to albumin. FSGS recurred in 11 of 13 children who tested positive for the permeability factor and in 4 of 12 patients with a negative test result; the odds ratio for developing recurrence was 10.99 (95% confidence limit, 1.6 to 75.47) in the former group. The immediate onset of proteinuria after transplantation was a negative prognostic factor for the outcome; 6 of 9 patients in whom proteinuria appeared within 2 days of transplantation returned to dialysis in less than 24 months. In 9 of 11 patients who were treated with plasmapheresis plus cyclophosphamide after recurrence, proteinuria was successfully reversed and persistent remission was obtained in 7 patients. These data show that the glomerular permeability test has a significant predictive value for the recurrence of proteinuria in children with FSGS who have received a renal allograft. Of the clinical parameters considered, only the duration of disease was significantly different in patients with recurrent versus nonrecurrent FSGS. Treatment with plasmapheresis plus cyclophosphamide can be effective in the control of FSGS relapse after renal transplantation.