A prospective observational study investigated whether two interferon-stimulated gene expression scores could predict progression to autoimmune connective tissue disease in at-risk individuals (antinuclear antibody-positive). Of 118 patients, 19 progressed to disease. Both interferon scores were increased in these at-risk individuals who went on to develop disease. Patients who progressed to disease did not have different baseline clinical characteristics or ultrasonography findings compared with patients who did not progress to disease. These interferon scores may enable early intervention for disease prevention.