The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45-64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p = 0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide less than or equal to 0.60 nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.