Patients diagnosed with the antiphospholipid syndrome typically suffer from vascular thrombosis, pregnancy morbidity, or a combination of the two. Due to the high prevalence of these clinical symptoms, the diagnosis of antiphospholipid syndrome is almost completely dependent on the detection of antiphospholipid antibodies in patient plasma. However, not every individual with antiphospholipid antibodies in his or her plasma suffers from thrombosis and/or pregnancy morbidity, which suggests the existence of different populations of antiphospholipid antibodies. Although many antigens have been identified in relation to the antiphospholipid syndrome, β2-glycoprotein I is regarded as clinically most significant. During the past decade, evidence has accumulated to suggest the presence of a dominant epitope on the first domain of β2-glycoprotein I. Several studies have detected a specific population of antibodies recognizing a cryptic epitope on domain I, at least comprising arginine 39 to arginine 43. In contrast to antibodies recognizing other domains of β2-glycoprotein I, anti-domain I antibodies are found to be highly associated with clinical symptoms. This review discusses several studies that have investigated a role for domain I within the antiphospholipid syndrome on a predominantly diagnostic level.