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Deuterated water (²H₂O) is a widely used tracer of carbohydrate biosynthesis in both preclinical and clinical settings, but the significant kinetic isotope effects (KIE) of²H can distort metabolic information and mediate toxicity.¹⁸O‐water (H₂¹⁸O) has no significant KIE and is incorporated into specific carbohydrate oxygens via well‐defined mechanisms, but to date it has not been evaluated in any animal model. Mice were given H₂¹⁸O during overnight feeding and¹⁸O‐enrichments of liver glycogen, triglyceride glycerol (TG), and blood glucose were quantified by¹³C NMR and mass spectrometry (MS). Enrichment of oxygens 5 and 6 relative to body water informed indirect pathway contributions from the Krebs cycle and triose phosphate sources. Compared with mice fed normal chow (NC), mice whose NC was supplemented with a fructose/glucose mix (i.e., a high sugar [HS] diet) had significantly higher indirect pathway contributions from triose phosphate sources, consistent with fructose glycogenesis. Blood glucose and liver TG¹⁸O‐enrichments were quantified by MS. Blood glucose¹⁸O‐enrichment was significantly higher for HS versus NC mice and was consistent with gluconeogenic fructose metabolism. TG¹⁸O‐enrichment was extensive for both NC and HS mice, indicating a high turnover of liver triglyceride, independent of diet. Thus H₂¹⁸O informs hepatic carbohydrate biosynthesis in similar detail to²H₂O but without KIE‐associated risks.