Regardless of type, uncontrolled diabetes represents a serious disruption of fuel homeostasis with consequences throughout the body. This may hamper the applicability of predeposited autologous blood transfusion in diabetic patients because metabolic changes are expected as a consequence of repeated bleeding. We undertook this study to determine whether the presence of non-insulin-dependent diabetes mellitus (NIDDM) influences the erythropoietin (EPO) response to repeated phlebotomies with respect to normal subjects. We included 22 consecutive patients scheduled for major surgery during a 2-year period in which clinical and metabolic complications were excluded and renal and liver function was considered unaffected. Selected biochemical and hematologic variables were serially measured during donation of several units of blood in a 12- to 29-day period. Bleeding produced a significant decrease in serum glucose, cholesterol, triglyceride, and apoprotein B concentration in diabetic patients. Except for glucose, this effect was not observed in controls. Both groups were comparable with respect to initial hemoglobin concentrations and all hematologic variables measured. The decrease in hemoglobin concentration did not produce clinical symptoms in these patients, and recovery was regarded as normal in both groups. Serum EPO levels in diabetic patients were negatively influenced by the initial hemoglobin A1c (HbA1c) proportion. Moreover, three nonrespondent diabetic patients with poor glycemic control responded normally 6 to 13 months later, in a second operation, when glycemic control had improved significantly. In conclusion, NIDDM may limit the donation of requested units for major surgery only if poor glycemic control is present. When possible, phlebotomies should be delayed and metabolic control reinforced.