Background: Cerebral ischemia and its mimics are often difficult to differentiate. While MRI is the gold standard for stroke diagnosis, a marker for TIA remains elusive. Proteomics offers a unique method to identify biomarkers of ischemic disease. Through the use of mass spectrometry-based proteomics, we analyzed the serum of patients with transient neurologic symptoms in our emergency department to determine candidate proteins to serve as indicators of cerebral ischemia. Methods: Patients with transient neurologic symptoms were prospectively enrolled and their serum was obtained. Mass spectrometry was performed on the samples, and the results were searched against the Human Uniport database to identify the most likely proteins. The student’s t-test was utilized to compare protein levels between the different clinical conditions, and significance was determined by using the Benjamini-Hochberg false discovery rate (FDR) controlling procedure for multiple comparison adjustments. Results: Twenty patients with TIAs, fifteen patients with minor strokes, and twelve control patients (i.e. migraine, seizure) were enrolled. Ceruloplasmin (p = 0.00027) and complement component C8 gamma chain (p = 0.00105) were increased in TIA and minor stroke compared with the control group, while platelet basic protein (p = 0.00010) was decreased. TIA patients tended to have higher Ig kappa chain 6 region AG and platelet basic protein levels and lower apolipoprotein F levels than stroke patients (p <0.05), but these differences were not significant after FDR adjustments. Conclusions: Mass spectroscopy-based proteomics is a potential new tool to help identify biomarkers for cerebral ischemia. Ultimately, a panel of proteins may serve as a marker for cerebral ischemia or TIA. We have identified three candidate proteins as possible indicators for cerebral ischemia. Larger studies are needed to confirm our results.