There is a spectrum of glomerular pathology in patients with severe lupus glomerulonephritis (GN) that includes (1) severe segmental GN (SEG) with greater than or equal to 50% of glomeruli involved by active segmental inflammation, (2) diffuse GN, and (3) membranous GN with associated severe SEG or diffuse GN (MGN + PGN). The clinical and laboratory characteristics at entry and at follow-up of 85 patients in a prospective therapeutic trial of plasmapheresis were examined to determine if these morphologic variants had prognostic implications. Addition of plasmapheresis to the therapeutic regimen did not affect outcome, and the two treatment groups were analyzed together. Patients with the three patterns of lupus GN were similar demographically and clinically, and they had similar serum creatinines at entry (SEG, 1.87 +/- 0.28 mg/dL [mean +/- SE], v diffuse GN, 2.11 +/- 0.21, v MGN + PGN, 2.12 +/- 0.26; P = 0.75). Although significant differences were found in the initial serum C3 (SEG, 46 +/- 5 mg/dL, v diffuse GN, 34 +/- 3, v MGN + PGN, 45 +/- 3; P = 0.02) and urinary protein excretion (SEG, 3.6 +/- 0.6 g/24 h, v diffuse GN, 6.0 +/- 0.7, v MGN + PGN, 6.7 +/- 0.9; p = 0.03), none of the clinical or laboratory data predicted the morphologic pattern of the glomerular lesion. Adverse outcomes included defined clinical stop points, nonfatal renal failure, and death. One half of the patients with MGN + PGN (13/26) had an adverse outcome, compared with 5/24 patients with SEG and 11/35 patients with diffuse GN. This trend was supported by actuarial analysis of outcomes showing that patients with MGN + PGN had the lowest cumulative proportion without adverse outcome after 175 weeks of follow-up (MGN + PGN, 0.40, v SEG, 0.77, v diffuse GN, 0.64; P = 0.04). We concluded that (1) at presentation, the specific glomerular lesion in severe lupus GN cannot be predicted on clinical or serological criteria alone; (2) on the basis of morbidity and mortality, cases with all three morphologic variants should be classified as severe lupus GN; and (3) patients with MGN + PGN appear to experience more adverse outcomes than patients with SEG or diffuse GN.