<p>Sarcosine has been reported to improve ischemic tolerance in animal models of brain ischemia, but population-based evidence from patients with ischemic stroke is lacking. We conducted a multicenter prospective study to investigate the associations between plasma sarcosine levels and adverse outcomes among patients with ischemic stroke. We measured plasma sarcosine levels among 3473 patients with ischemic stroke from 26 hospitals across China. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale [mRS] score, 3–6) at 3 months after ischemic stroke. Secondary outcomes were major disability (mRS score, 3–5), death (mRS score, 6), and cardiovascular events. During 3 months of follow-up, 853 participants experienced the primary outcome. Compared with the lowest quartile of sarcosine, the multivariable-adjusted odds ratios or hazard ratios of the highest quartile were 0.59 (<i>P</i>_trend &lt; 0.001) for primary outcome, 0.70 (<i>P</i>_trend = 0.002) for major disability, 0.20 (<i>P</i>_trend &lt; 0.001) for death, and 0.43 (<i>P</i>_trend = 0.017) for cardiovascular events. Multivariable-adjusted spline regression model showed linear associations of sarcosine with adverse outcomes (all <i>P</i>_linearity &lt; 0.05). Adding sarcosine to conventional prognostic factors modestly improved the risk reclassification of adverse outcomes after ischemic stroke, as evidenced by net reclassification improvement and integrated discrimination improvement (all <i>P</i> &lt; 0.05). Additionally, there was a strong combined effect of sarcosine and glycine on the risks of adverse outcomes after ischemic stroke. High plasma sarcosine levels were associated with low risks of adverse outcomes after ischemic stroke, suggesting that sarcosine might serve as a valuable prognostic biomarker for ischemic stroke.</p>