This is a case of IgG4-related systemic disease (ISD) and its rare renal manifestation as membranous nephropathy (MGN). The patient presented with peripheral edema, hematuria and proteinuria. 24-h urine revealed proteinuria of up to 15 g/d. Renal biopsy revealed MGN and many IgG4-positive plasma cells. Serum IgG4 levels were elevated at 750 mg/dl (9 - 89 mg/d). Biopsies of multiple tissues revealed many IgG4-positive plasma cells. Prednisone was initiated after making the diagnosis of ISD. However, the patient progressed into renal failure and eventually needed dialysis despite rituximab therapy. The renal manifestation of ISD typically shows tubulointerstitial nephritis, but, rarely, it may include glomerular abnormalities such as MGN or membranoproliferative glomerulonephritis. Castleman disease (CD) and ISD share similarities in pathology, particularly in the lymph nodes. Rituximab has shown promising results in some patients with ISD, CD, and MGN, and its use should be considered in steroid-resistant cases. Clinicians need to be made aware of ISD and its varied presentations. Timely initiation of steroid therapy can induce remission, and delay in therapy can cause permanent organ damage. Therefore, clinicians must have a high index of suspicion to make an early diagnosis of ISD in order to initiate appropriate treatment.