Mice deficient in adipose triglyceride lipase (ATGL^−/−) present elevated ectopic lipid levels but are paradoxically glucose-tolerant. Measurement of endogenous glucose production (EGP) and Cori cycle activity provide insights into the maintenance of glycemic control in these animals. These parameters were determined in 7 wild-type (ATGL^+/−) and 6 ATGL^−/−mice by a primed-infusion of [U-¹³C₆]glucose followed by LC-MS/MS targeted mass-isotopomer analysis of blood glucose. EGP was quantified by isotope dilution of [U-¹³C₆]glucose while Cori cycling was estimated by analysis of glucose triose¹³C-isotopomers. Fasting plasma free fatty-acids were significantly lower in ATGL^−/−versus control mice (0.43 ± 0.05 mMversus0.73 ± 0.11 mM,P<0.05). Six-hour fasting EGP rates were identical for both ATGL^−/−and control mice (79 ± 11versus71 ± 7 μmol/kg/min, resp.). Peripheral glucose metabolism was dominated by Cori cycling (80 ± 2% and 82 ± 7% of glucose disposal for ATGL^−/−and control mice, resp.) indicating that peripheral glucose oxidation was not significantly upregulated in ATGL^−/−mice under these conditions. The glucose¹³C-isotopomer distributions in both ATGL^−/−and control mice were consistent with extensive hepatic pyruvate recycling. This suggests that gluconeogenic outflow from the Krebs cycle was also well compensated in ATGL^−/−mice.