Background <p>Erythritol is a non-nutritive sweetener that is also endogenously produced from glucose. We investigated whether declines in plasma erythritol and other sugar alcohols (polyols) in response to weight-loss dietary interventions were significantly associated with long-term improvements in glucose metabolism and insulin sensitivity.</p> Methods <p>Plasma erythritol, mannitol/sorbitol, and arabitol/xylitol were repeatedly measured among adults with overweight or obesity who participated in the POUNDS Lost trial (<i>n</i> = 802 at baseline and <i>n</i> = 664 at 6 months). We analyzed associations of changes in erythritol, mannitol/sorbitol, and arabitol/xylitol from baseline to 6 months with changes in homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, fasting glucose, and HbA1c at 6 months and 2 years of intervention.</p> Results <p>Plasma erythritol levels were positively related to HOMA-IR, fasting insulin, and glycemic markers at baseline. Greater declines in plasma erythritol in response to the interventions were associated with greater reductions in HOMA-IR (<i>p</i> &lt; 0.001) and fasting insulin (<i>p</i> &lt; 0.001) at 6 months. Similar associations were found for changes in arabitol/xylitol, but not for mannitol/sorbitol. Every 1 SD reduction in plasma erythritol during the initial 6-month period was related to long-term (2-year) decreases in log-transformed HOMA-IR (β [SE] –0.07 [0.02], <i>p</i> = 0.008) and glycemic markers (β –1.0 [0.44] mg/dL, <i>p</i> = 0.025 for fasting glucose; β –0.05% [0.02%], <i>p</i> = 0.019 for HbA1c).</p> Conclusion <p>Declines in plasma erythritol may be related to long-term improvements in insulin sensitivity and glycemic status during weight-loss dietary interventions in adults with overweight or obesity.</p>