In a prospective study to evaluate the prevalence and predictive potential of circulating cytoplasmatic islet cell antibodies (ICA) and competitive insulin autoantibodies (CIAA), we screened 406 non-diabetic first-degree relatives of patients with Type I diabetes mellitus (n = 154 for CIAA). The prevalence of ICA was 2.5% (10/406) and of CIAA 0.6% (1/154) in ICA- and 10% (1/10) in ICA+ relatives at initial screening. The titer of ICA positivity in all relatives varied between 1:1 and 1:4. Values of elevated CIAA were 256 nU/ml of the CIAA+/ICA+, and 97 nU/ml of the CIAA+/ICA- relatives (normal range less than or equal to 39 nU/ml). Sera for repeat ICA and CIAA determination was obtained, and 70% of relatives were found to be again ICA+ after 1.5 years, 40% after 3 years, and 10% after 5.7 years. Both CIAA+ relatives were found to be again CIAA+ on follow-up. Intravenous glucose tolerance tests (IVGTT) were performed in all antibody-positive relatives. No decrease in first-phase insulin secretion (1 + 3 min) below the 1st percentile was observed in any of the ICA+ relatives during follow-up. No ICA+, but one CIAA+/ICA- relative had developed Type I diabetes after 5.6 years of follow-up. In summary, these results indicate that low titer ICA (less than 40 JDF units) are often transient and relatives with low titer ICA rarely progress to Type I diabetes. Elevated CIAA appear to be constant over time and associated with increased progression to overt diabetes.