During the past 15 years, the clinical spectrum associated with the anti-Ro(SS-A) antibody response has been defined. Various clinical presentations, including subacute cutaneous lupus erythematosus, the neonatal lupus syndrome, the Sjögren's syndrome/lupus erythematous overlap syndrome, and primary Sjögren's syndrome, have been detected in association with the anti-Ro(SS-A) response. The anti-Ro(SS-A) antibody response is associated with the HLA-DR2 and HLA-DR3 phenotypes. There is now a good deal of evidence to suggest that many anti-Ro(SS-A)-positive HLA-DR3 women are genetically closely related, sharing in common an enriched frequency of the HLA-DR3-linked B8, DQw2, and DRW52 phenotypes. DNA sequence studies have confirmed this genetic relationship. These studies have led us to the following conclusions. 1) The HLA-DR2 and HLA-DR3 associations with systemic lupus erythematosus and the HLA-DR3 association with Sjögren's syndrome are related to the anti-Ro(SS-A) antibody response and not to the clinical disease expression. 2) HLA-DR3 anti Ro-positive female patients with first-degree Sjögren's syndrome, subacute cutaneous lupus erythematosus, or Sjögren's syndrome, or who are asymptomatic, are immunogenetically closely related even though the clinical presentations are strikingly different. All these HLA-DR3 anti-Ro(SS-A) antibody-positive women are at risk to give birth to a child with the neonatal lupus syndrome.