To evaluate the predictive factors of insulin requirement in newly diagnosed patients with unclassifiable diabetes, 54 consecutive patients, aged less than 35 years, were prospectively followed for 3 years or more. At entry, haemoglobin HbA1c, basal and stimulated C-peptide concentrations, HLA phenotype, islet cell antibodies (ICA) status, and serum levels of soluble CD8 antigen (sCD8) were evaluated. After a median time of 9 (range 2-32) months, 31 patients (group 1) required insulin therapy, whereas 23 patients (group 2) remained non-insulin-requiring after 36 months. Group 1 patients were younger (P < 0.05) and had higher HbA1c and sCD8 serum levels (P < 0.0001), respectively), a higher frequency of ICA positivity and of HLA DR3 and/or DR4 phenotype (P < 0.005 and P < 0.0001, respectively), and lower C-peptide concentrations (P < 0.005 and P < 0.0001, basal and stimulated, respectively) than group 2. The sensitivity, specificity, positive and negative predictive value, and overall accuracy for the subsequent insulin requirement were: sCD8 serum levels (> 737 U/ml), 100%, 65%, 79%, 100% and 85%, respectively; stimulated C-peptide (< 0.60 nmol/l), 71%, 96%, 96%, 74% and 81%, respectively; and ICA positivity (> 20 JDFU), 45%, 91%, 87%, 55% and 65%, respectively. Thus, higher sCD8 serum levels, low stimulated C-peptide concentrations and ICA positivity are the most powerful predictors of subsequent recourse to insulin therapy in young, newly detected patients with unclassifiable diabetes.