Membranoproliferative glomerulonephritis (MPGN) is classified as type I, II, or III based on ultrastructural alterations in the glomerular basement membrane. Whereas type II has long been recognized as clinically and pathologically unique, types I and III are often difficult to distinguish and have not been separated in most clinical studies. We compared the course and long-term outcome of patients with types I and III MPGN followed up at this institution since 1960. During this period, 21 patients with type I and 25 patients with type III were followed up for a minimum of 5 years. Patients with types I and III MPGN did not differ in age at apparent onset, age at diagnosis, or interval from apparent onset of symptoms to diagnosis (biopsy). They had similar initial serum C3 and serum albumin levels. Patients with type I had a significantly lower initial mean estimated glomerular filtration rate (GFR(est)) compared with those with type III (99.1 +/- 35.9 versus 131.6 +/- 36. 1 mL/min/1.73 m(2); P < 0.01). Type and duration of therapy, length of follow-up, and frequency of complications of therapy did not differ between groups. There was, however, a significant difference in duration of hypocomplementemia. After 1 year of an alternate-day prednisone regimen, 90% of the type I patients normalized their serum C3 levels compared with less than 50% of type III patients (P < 0.01). After 3 years of therapy, only 5% of type I patients were hypocomplementemic compared with 33% of type III patients (P < 0.02). In addition, disease relapse occurred in six type III patients (24%) compared with no type I patients. At last follow-up, type I patients had a slight improvement in mean GFR(est) (+6.3 +/- 48.4 mL/min/1.73 m(2)), whereas type III patients had a 25% decrease in mean GFR(est) (-34.8 +/- 47.6 mL/min/1.73 m(2); P < 0.01). Residual urinary abnormalities were significantly more frequent in patients with type III than type I MPGN. Hematuria persisted in 72% versus 38% (P < 0.05) and proteinuria in 28% versus 0% (P < 0.01) of those with types III and I, respectively. These results give clear evidence of significant differences in the clinical progression of the two types and their response to the alternate-day prednisone regimen. Whereas the outcome of patients with type I MPGN treated with alternate-day prednisone was generally good, similarly treated patients with type III experienced significant reductions in renal function, slower improvement in serum C3 levels, more persistent urinary abnormalities, and more frequent relapses.