Familial focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal disease characterized by proteinuria and an unremitting deterioration of renal excretory function. Previous studies showed corticosteroid unresponsiveness and a variable response to cyclophosphamide therapy. We hypothesized that treatment with pulse methylprednisolone therapy (PMT), alternate-day corticosteroids, and cyclosphosphamide or cyclosporine would decrease proteinuria in patients with familial FSGS. Two adolescent brothers, 13 and 16 years old, presented with nephrotic range proteinuria, but with normal renal excretory function. Both brothers had renal biopsies that showed FSGS with mesangial hypercellularity and tubular atrophy. Intravenous PMT, at doses of 1 g, was initiated per the Tune-Mendoza protocol. Both patients received lisinopril therapy. One brother (case 1) was treated with PMT, alternate-day corticosteroids, and cyclophosphamide (total cumulative cyclophosphamide dose was 154.3 mg/kg). Urinary protein-to-urinary creatinine (UP/UC) ratios decreased from 6.79 to 3.79. Cyclosporine therapy decreased the UP/UC further from 2.48 to 0.76 at the end of PMT. The other brother (case 2), treated with PMT, alternate-day corticosteroids, and cyclosporine, experienced a decrease in UP/UC from 7.27 to 1.14. At the time of last evaluation, approximately 7 months after the last PMT dose, the UP/UC ratios were 0.27 (case 1) and 0.37 (case 2). PMT-attributable adverse effects were not severe. Both patients continued to receive oral cyclosporine and lisinopril after completion of PMT. PMT and cyclosporine therapy may reduce proteinuria, without decreasing renal excretory function, in some patients with familial FSGS. Further evaluation of cyclosporine therapy and PMT of patients with familial FSGS is warranted.