We compared the frequency of immunoglobulin G (IgG) type of human leukocyte antigen (HLA) class I antibodies between patients with systemic lupus erythematosus (SLE) and healthy controls using a highly sensitive FlowPRA method. Sixteen of 130 normal healthy males and 2 of 10 normal females without a history of pregnancy (none had ever been transfused) possessed HLA class I antibodies. In SLE, male, but not female patients, showed a significant increase in the frequency of the antibodies compared with the corresponding controls. The antibodies did not appear to be involved in the development of SLE because of no substantial relationship to the incidence of cytopenia or SLE disease activity index score. Each individual had 1-31 types of HLA class I antibodies. Interestingly, HLA class I antibodies did not correspond to the individual's own HLA antigens. Eight of 32 types of HLA class I antigens detected were rare in the Japanese population. These results suggest that an IgG component of naturally occurring HLA class I antibodies exists in human serum and that these antibodies are not antibodies against self-antigens.