The goal of this nested case-control study was to compare autoantibody profiles in systemic lupus erythematosus (SLE) patients with lupus nephritis (LN), lupus nephritis patients requiring renal transplantation (LNTP) and a SLE control group without nephritis (CON). Sera were assayed for a variety of autoantibodies by addressable laser bead immunoassay (ALBIA) and enzyme-linked immunoassay (ELISA) and to dsDNA by Crithidia luciliae assay. The frequency of nucleosome autoantibodies was significantly greater in the LNTP group (79%) compared to the LN (18%) and CON (9%) groups (P < 0.0005). The frequency of other autoantibodies, including anti-dsDNA, did not differ significantly between groups. Among patients with LN, the odds of progressing to renal transplantation was 16-fold higher (OR 16.5 [95% CI 2.5, 125.7], P = 0.0005) in patients testing positive for anti-nucleosome antibodies compared to those who tested negative. Furthermore, the level of anti-nucleosome antibodies was significantly ( P < 0.00005) higher in the LNTP group (3.69 +/- 2.79) than the LN (0.51 +/- 0.51) and CON (0.34 +/- 0.44) groups. Review of 48 renal biopsies from 29 patients indicated that there was no difference in renal histological classification among patients with anti-nucleosome antibodies compared to those who tested negative. Our observations suggest that nucleosome autoantibodies are a biomarker for more severe SLE renal disease requiring transplantation.