We determined the serum concentrations of tumor necrosis factor (TNF) in 15 nondiabetic healthy subjects and in 36 insulin-dependent (type I) diabetic outpatients. The mean (+/- SD) annual fasting plasma glucose, urine glucose and HbA1 levels of the diabetic group were 179 +/- 71 mg/dl, 13.0 +/- 13.2 g/day and 12.3 +/- 1.3%, respectively. The mean serum TNF concentration measured by immunoradiometric assay of the diabetic group (8.6 +/- 1.9 pg/ml) was significantly higher than healthy controls (6.9 +/- 0.9 pg/ml). Within the diabetic group, there was no correlation between serum TNF levels and either duration of diabetes or indices of metabolic control. However, serum TNF levels progressively increased from the well to the poorly controlled diabetic groups: 8.1 +/- 1.5 (G), 8.2 +/- 1.4 (F) and 9.4 +/- 2.4 (P) pg/ml, respectively, which parallel levels of HbA1 (%): 8.4 +/- 2.4, 11.7 +/- 1.8 and 14.6 +/- 1.2, respectively. Serum TNF levels of the diabetic patients with chronic complications (N = 7, 9.5 +/- 2.3 pg/ml) and without complications (N = 29, 8.4 +/- 1.7 pg/ml) were statistically higher than control subjects. The progressive increase of the serum TNF levels from the well to the poorly controlled diabetic groups suggests a relationship between levels of this cytokine and protein glycosylation.