Abstract Purpose: Evaluation of orbital blood flow parameters by using color Doppler imaging in patients with unilateral exfoliation syndrome (XFS). Methods: This prospective, comparative case series included 33 unilateral XFS patients, and 33 age‐sex matched control subjects. Color Doppler imaging was used to evaluate the XFS affected (Group 1), and unaffected (Group 2) eyes that were matched with the corresponding side (Groups 3, and 4) of control subjects. A masked radiologist obtained peak systolic velocity (PSV), and end diastolic velocity (EDV) of ophthalmic (OA), central retinal (CRA), nasal posterior ciliary (NPCA) and temporal posterior ciliary arteries (TPCA) as well as mean velocity of central retinal vein (CRV). Resistive indices (RI) were calculated. Results: Orbital blood flow parameters had no statistically significant difference between Group 1, and 2 (p>0.05). OA of Group 1 had significantly low PSV and EDV, and high RI compared to Group 3. OA PSV, EDV, and RI for Groups 1, and 3 were 25.3+/‐9.2 cm/sec (p=0.000), 5.8+/‐2.5cm/sec (p=0.000), 0.74+/‐0.04 (p=0.009), and 35.1+/‐11.0 cm/sec, 9.7+/‐3.5 cm/sec, 0.69+/‐0.07 respectively. The RI had a cut‐off value of 0.72 between Group 1 (95% Confidence Interval [CI] for mean, 0.72‐0.75) and Group 2 (95% CI, 0.66‐0.72). In Group 2, OA PSV and EDV also were lower than Group 4 while the RI value did not differ significantly. Blood flow values for CRA, NPCA, TPCA, and CRV did not show any significant difference between the groups (p>0.05). Conclusions: Ophthalmic artery hemodynamic parameters change in both eyes of unilateral XFS patients pointing out the systemic nature of the disease. The decrease in blood flow might be due to decreased vascular compliance through progressive buildup of exfoliative material in blood vessels.