The effect of a lipid infusion on postabsorptive glucose metabolism was investigated in non-insulin-dependent diabetes mellitus (NIDDM) patients. During a basal period, plasma free fatty acids (FFA) and triglycerides, postabsorptive glycemia and insulinemia, and glucose turnover and metabolic clearance rates (MCRs) were measured in 10 NIDDM patients. After the basal measurement, five patients received a lipid infusion, and the others received saline. Lipid infusion prevented the decrease in postabsorptive glycemia observed in the saline group (P < .01). The principal mechanism for this effect was a reduction in glucose MCR (30.8 +/- 5.7 v 47.2 +/- 3.4 mL/m2/min, P < .05), which was absent in control tests (50.4 +/- 8.1 v 47.9 +/- 4.7 mL/m2/min, NS). The absence of the compensatory insulin release observed in normal subjects may play a role in this response. The prolonged postabsorptive hyperglycemia induced by lipid infusion in NIDDM patients is further evidence for the detrimental effect of the lipid-carbohydrate interactions described by Randle.