Previous reports suggest a protective role for anti-La autoantibody against the development of lupus nephritis. We studied the effect of anti-La on the prevalence of nephritis in a large cohort of lupus patients. In addition, we determined the association between anti-La and the presence of the various other lupus manifestations. We studied 1100 lupus patients enrolled in the Lupus Family Registry and Repository. Only one lupus patient per family was selected to exclude intrafamilial correlation. Since anti-La is present in patients who also have anti-Ro autoantibody, we compared anti-Ro positive lupus patients in the presence or absence of anti-La. Clinical data were obtained from medical records, interviews and participant questionnaires. Tests for autoantibodies against extractable nuclear antigens were performed using immunodiffussion assays. There is no difference in the age, sex or race between the anti-La positive and anti-La negative lupus patients. The presence of anti-La is associated with a significant reduced risk of lupus nephritis (proteinuria: 29.3% versus 46.3%, OR = 0.48, P = 0.023; cellular casts: 8.6% versus 20.6%, OR = 0.36, P = 0.038). In addition, lupus patients with anti-La have a reduced risk for seizures (0% versus 10.9%, P = 0.0096) and are more likely to have arthritis (79.3% versus 64.0%, OR = 2.16, P = 0.031). The presence of anti-nRNP autoantibody is significantly reduced in anti-La positive compared with anti-La negative lupus patients (10.3% versus 27.4%, OR = 0.31, P = 0.0075). In conclusion, anti-La autoantibody is associated with less severe lupus. Patients with anti-La have a lower risk of renal involvement and seizures compared with anti-La negative lupus patients.