In order to evaluate the expression of antinuclear antibodies (ANA) in normal elderly individuals over time and clinical significance, a cross-sectional ANA testing in healthy Japanese was performed, followed by annual evaluations of ANA positive aged (> or = 65 years) and a control group. ANA was more prevalent in the aged (11.4% vs. 3.8%) and most were persistent after 4 years. Anti-ssDNA and anti-histone antibodies were increased in aged ANA positive as compared to ANA negative controls. Except for a history of spontaneous abortion, there was no differences in clinical findings. HLA DRB1*0901 and the DQB1*0602 + 0302 + 0303 set of alleles were increased in ANA positive. Therefore, ANA in the aged were persistent, apparently directed toward chromatin elements, and shared MHC associations with autoimmune diseases. Longer follow-up may be necessary to improve the evaluation of clinical significance of ANA in the aged.