Proteinuria and nephrotic syndrome due to recurrent disease may develop after renal transplant in patients with focal glomerular sclerosis (FGS). The rapid onset of proteinuria in many of these patients suggests a possible humoral mediator. We studied serum from a patient who has had recurrence of nephrotic syndrome and FGS after two cadaveric renal allografts to determine if a serum factor capable of producing increased urinary protein excretion was present. Serum was infused into the aorta of anesthetized rats. During infusion of serum from the patient with recurrent FGS, there were significant increases in mean urinary protein and rat albumin excretion which persisted after infusion. When sera from ten patients with nephrotic syndrome secondary to other glomerulopathies were infused no changes in urinary protein or albumin excretion were noted. Likewise no changes in urine protein or albumin excretion were produced with infusion of serum from a patient with FGS without recurrence after transplantation. Increases in urine protein and albumin excretion noted during and after infusion of recurrent FGS serum were independent of changes in glomerular filtration rate, urine volume, or fractional excretion of sodium. These results suggest there is a factor or factors present in the serum of this patient capable of producing enhanced urinary protein excretion in the rat. This factor(s) which is heat stable at 56 degrees C could possibly play a role in the pathogenesis of recurrent nephrotic syndrome.