We have evaluated the autoantibody profiles in the sera of 117 patients with systemic lupus erythematosus (SLE) and compared and contrasted the clinical and laboratory features of the disease of patients segregated according to an autoantibody profile. Using this approach we are able to demonstrate that autoantibody profiles identified subsets of patients with SLE. Patients with a negative autoantibody profile had fewer clinical and laboratory features of their disease when compared to the other subsets of patients. In contrast, patients with profile A (anti-nDNA and/or anti-Sm antibodies) had a statistically significant increase in malar rash, renal and hematologic involvement and hypocomplementemia when compared to patients with a negative profile. Patients with profile B (anti-nRNP antibodies) had a clinical pattern of disease different from that of patients with profile A and had a statistically significant increase in Raynaud's phenomenon when compared to patients with a negative profile. Patients with profile C (anti-SSA and/or anti-SSB antibodies) had a statistically significant increase in lupus-related rashes and photosensitivity. None of the lupus patients reviewed in this study has profile D (antibodies to centromere and/or Scl-70), this profile being seen largely in patients with scleroderma or one of its variants. Both patients with profile E (anti-histone antibodies) had drug-induced lupus. We conclude that the use of autoantibody profiles defines subsets of patients with lupus that may have clinical, therapeutic and prognostic implications.