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BACKGROUND The present study analyzed the relationship between circulating Trimethylamine N-oxide (TMAO) levels and stroke severity in diabetic patients with acute ischemic stroke. A further aim was to investigate whether higher TMAO levels were associated with platelet aggregation and glycemic variability. METHODS This was a cross-sectional analysis of 108 patients with type 2 diabetes mellitus (DM) undergoing acute ischemic stroke and 60 healthy controls. Fasting plasma TMAO was measured using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. RESULTS Plasma TMAO levels of patients with acute ischemic stroke were significantly higher than those of healthy controls. Among stroke patients, 50 were defined as undergoing mild stroke, and their plasma TMAO levels were lower compared to those with moderate to severe stroke. Platelet aggregation and mean amplitude of glycemic excursions (MAGE) were both correlated with plasma TMAO levels and these relationships remained significant in multiple linear regression analyses. Moreover, in streptozotocin-induced diabetic rats fed a diet enriched with choline to increase TMAO synthesis, platelet aggregation was significantly increased in the DM+choline and fluctuated DM (FDM)+Choline groups compared to the Control group. This increase was abolished in rats receiving oral ABS, which markedly reduced plasma TMAO levels. Importantly, compared with the DM+choline group, the FDM+Choline group displayed significantly elevated TMAO levels and higher platelet aggregation. CONCLUSIONS Our results demonstrated that higher plasma TMAO levels were associated with stroke severity and suggested a novel link between plasma TMAO levels and glycemic variability in diabetic patients with acute ischemic stroke.