Objective: Ischemic stroke (IS) is one of the major causes of disability and death worldwide. Effective prevention remains the best approach to reduce the burden of stroke. Adipokines can serve as a key messenger to central energy homeostasis and metabolic homeostasis. Retinol-binding protein 4 (RBP4), a retinol transporter, is elevated in insulin resistance. Controversy exists regarding the role of RBP4 in thyroid diseases. the objective of this study was to evaluate serum RBP4 in patients with hypothyroidism and to assess the association of serum RBP4 with susceptibility of ischemic stroke Subject and methods: This case-control study included 50 healthy control group and 90 patients with hypothyroidism were stratified into two subgroups; patients with stroke group (n=30) and Non-stroke group (n=60) All subjects were subjected to history taking, clinical, laboratory, and radiological evaluation. Stroke severity within 72 hours of the onset of symptoms was assessed using the National Institute of Health Stroke Scale (NIHSS) Results: Serum RBP4 levels were significantly higher in hypothyroid patient especially patients with IS compared to the non-stroke group. Interestingly, serum RBP4 level was positively correlated with vascular and metabolic risk factors. Also, diastolic and systolic blood pressure, TG, FT3, as well as TSH, were independently correlated with serum RBP4 by linear regression analysis test. The diagnostic power of serum RBP 4 level in differentiating hypothyroidism from controls, the cutoff values were 12.25 and the area under the curve (AUC) was 0.909 (95% CI = 0.861–0.957). While the diagnostic power of serum RBP 4 level in differentiating hypothyroid patient with IS from the other without stroke, the cutoff values were 11.4 and the AUC was 0.822 (95% CI = 0.737–0.906). In conclusion, the higher levels of serum RBP4 levels in hypothyroidism especially in patients with IS, associated with metabolic and glucose abnormalities .and, thus, it could be a promising predictive biomarker of IS in hypothyroidism