Diabetes mellitus is a heterogeneous disease. The better classification of types of diabetes mellitus among adults will improve epidemiologic studies of determinants of risk factors and genetic host susceptibility. Recently, an antibody to a specific enzyme, glutamic acid decarboxylase, has been closely linked to insulin-dependent diabetes mellitus. Sera were collected at baseline between 1972 and 1974 from initially nondiabetic participants in the Multiple Risk Factor Intervention Trial. After approximately 18 years of frozen storage, the serum samples were tested for antibodies to glutamic acid decarboxylase (anti-GAD) in 175 men who developed diabetes and 352 matched controls who did not develop diabetes during the 6-year follow-up. Nine of the 527 samples tested had elevated (19 or more units) titers of anti-GAD. Six of the nine men with elevated anti-GAD subsequently developed diabetes, and three of these six were ultimately placed on insulin therapy. These data suggest that elevated levels of anti-GAD may be a prospective marker for the subsequent development of insulin-dependent diabetes mellitus. The measurement of anti-GAD is relatively easy, can be performed in stored serum specimens, and may be used in epidemiologic studies to enhance the understanding of the determinants of diabetes mellitus.