Atherosclerosis is the major complication of diabetes. Accumulating evidence indicates that lipoprotein lipase (LPL) produced by macrophages in the vascular wall may favor the development of atherosclerosis by promoting lipid accumulation within the lesion. We previously demonstrated that high glucose stimulates in vitro murine and human macrophage LPL production. In this study, we measured macrophage LPL mRNA expression, immunoreactive mass, and activity in normotriglyceridemic subjects with type 2 diabetes. Monocytes isolated from healthy control subjects and patients with type 2 diabetes were differentiated into macrophages in RPMI medium containing 20% autologous serum. After 5 days in culture, macrophage LPL mRNA expression, mass, and activity were determined. Macrophages of diabetic patients cultured in their own sera showed a significant increase in LPL mRNA levels, mass, and activity compared with macrophages of control subjects. Differentiation of macrophages of diabetic patients in sera obtained from control subjects significantly reduced these anomalies. Conversely, culturing macrophages of control subjects in sera of diabetic patients significantly increased LPL mass and activity in these cells. Besides LPL overproduction, macrophages of diabetic patients exhibited an increase in basal and LPL-induced tumor necrosis factor (TNF)-alpha release. TNF-alpha alterations were reduced by exposing these cells to sera of control subjects. Overall, these data demonstrate that macrophages of diabetic patients overexpress LPL and TNF-alpha and that peripheral factors dysregulated in diabetes are, at least in part, responsible for these alterations.