We compared continuous subcutaneous insulin infusion (CSII) versus multiple injections (MI) in the treatment of insulin-dependent diabetes mellitus (IDDM) to assess the effect of glucose control on monocyte insulin receptors. Each IDDM patient (n = 8) was treated for 2 mo by MI (HS Ultralente and AC boluses of regular insulin) and for 2 mo by CSII in a randomized fashion. Prestudy preprandial/postprandial blood glucose levels were 199 +/- 33/261 +/- 28 mg/dl and improved to 124 +/- 12/156 +/- 13 mg/dl during MI and to 115 +/- 11/151 +/- 11 mg/dl during CSII. Glycosylated hemoglobin before the study was 10.1 +/- 0.5% and decreased to 8.8 +/- 0.4 and 8.3 +/- 0.3% during MI and CSII, respectively. The specific 125I-labeled insulin binding to circulating monocytes in a group of nonobese controls (n = 17) was 4.6 +/- 0.2%. In our poorly controlled diabetics during conventional therapy, the 125I-insulin binding was decreased to 3.7 +/- 0.3 (P less than .025). This was not significantly affected by MI despite good glucose control (4.0 +/- 0.3%). With CSII, however, good glucose control was associated with normalization of 125I-insulin binding to monocytes (4.7 +/- 0.27%). The affinity of the insulin receptors was normal before the study and was not affected by either MI or CSII. In conclusion, these observations demonstrate that in IDDM, intensive therapy by MI and CSII resulted in similar good glucose control, but only CSII resulted in normalization of insulin receptors on circulating monocytes.