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Diabetics have a high risk of ischemic stroke. The present study aimed at evaluating the diagnostic validity of immediate measurements of serum S-100B and Neuron-Specific Enolase (NSE) in comparison with neurological examinations and cerebral computed tomography (CT) findings in diabetic ischemic stroke patients. It also aimed at determining the possible influence of type 2 diabetes mellitus, either or not complicated with stroke, on serum levels of S-100B and NSE. Another objective of the current study was the determination of serum malondialdehyde (MDA) as an indicator of lipid peroxidation (LPO) to detect any possible correlation between LPO and S-100B or NSE. This cross sectional study included 66 subjects; 46 diabetic patients and 20 healthy subjects. Participants were classified into the following groups: Group I: 25 diabetic patients (type 2) with acute stroke. Group II: 21 uncomplicated controlled type 2 diabetic patients. Group III: 20 apparently healthy age and sex matched control subjects. Serum levels of S-100B and NSE were assessed by ELIZA technique. MDA levels were measured using a chemical method. Results of this work showed that the mean levels of serum S-100B and NSE in diabetic patients with cerebrovascular stroke were significantly higher than the corresponding mean values in uncomplicated diabetic patients and in control subjects (P < 0.001). Serum S-100 B levels in diabetic stroke patients showed significant positive correlation with the infarct size as assessed by the CT brain (r = 0.9816 , P < 0.001). Similarly, serum levels of NSE correlated positively with infarct size (r = 0.9384, P < 0.001). No significant correlation was observed between levels of S-100B and NSE on one hand and glycemic control and duration of diabetes on the other. Also, MDA showed statistically significant elevation in diabetics with stroke compared to its corresponding values in uncomplicated diabetics and control groups (P < 0.001). In conclusion: Serum levels of S-100B and NSE correlated with the neurological clinical findings, as well as the infarct size as assessed by brain CT. So, S-100B and NSE measurements immediately after admission might help to reduce serial CT scans of the brain of ischemic stroke in diabetic patients. Future studies are recommended to follow the S-100B and NSE serum levels after thrombolytic therapy. Elevation of MDA in diabetic patients, which was significantly higher in diabetic patients complicated with stroke compared to uncomplicated diabetics, might direct the attention to further studies on the role of antioxidants in such patients.