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Background: Rapid identification and transport of patients with large vessel occlusions (LVO) to endovascular-capable hospitals has become increasingly important. We previously demonstrated that brain-specific sphingolipids (SLs) serve as useful plasma markers of brain injury. Here, we test and validate SL biomarkers to differentiate LVO from non-LVO acute ischemic stroke (AIS) and stroke mimics.Methods: We enrolled consecutive patients with symptoms concerning for AIS and performed SL profiling using HPLC-MS/MS on blood samples obtained at hospital arrival. MS data were aligned and automated peak picking was performed using XCMS, and SLs were identified by exact mass. A classification method using SL plasma concentrations was created using step-wise logistic regression in a derivation arm, and then tested in an independent validation arm.Results: Among 184 patients with AIS or AIS-mimics, 84 (46%) were female and age was 73 years (IQR 63-84). 81 (44%) were diagnosed with AIS, 32 (17%) with TIA, and 71 (39%) as stroke mimics. Median time from last known well to blood collection was 124 minutes (IQR 65-275) and Los Angeles Motor Scale was 1 (IQR 0-2). Among patients with AIS, median NIHSS was 3 (IQR 2-8) and 33 (41%) had LVO on CTA or MRA. Among 24 SLs definitively identified, 3 (12.5%) were ceramides, 3 (12.5%) were sphingosines, and 18 (75%) were sphingomyelins. Using step-wise regression, a panel of 8 SLs differentiated LVO from non-LVO AIS or stroke mimic with very good accuracy (AUC 0.76 in derivation; 0.72 in validation), comparable to LAMS alone (AUC 0.73). Combining the SL panel with LAMS resulted in superior discrimination (AUC 0.84 in derivation; 0.79 in validation and Figure).Conclusions: Plasma levels of SLs accurately differentiate LVO from non-LVO AIS and stroke mimics at early time points. A point-of-care SL assay in the field may help triage LVO patients to appropriate centers.