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Purpose: To determine the effect of intravenous mannitol on globe and orbital volumes. Methods: Retrospective chart review of a consecutive series of Cleveland Clinic Neurosurgical Intensive Care Unit patients who underwent computed tomographic imaging before and after intravenous mannitol administration. Volume measurements were performed according to a previously described technique by averaging axial image areas. Measurements before and after mannitol administration were compared using paired t-test. Results: Fourteen patients (28 eyes) met inclusion criteria. Average globe volume decreased 186 mm3 (-2.5%, p = 0.02) after mannitol administration, while average orbital volume increased 353 mm3 (+3.5%, p = 0.04). Average globe volume change for subjects with follow-up scan less than 4.7 hours (mean 1.9 hours; range 0.2-4.5 hours) after mannitol administration was -125 mm3 (-1.7%, p = 0.24) and average orbital volume change was +458 mm3 (+5.1%, p = 0.11). Average globe volume change after mannitol administration for those with follow-up more than 4.7 hours (average 13.9 hours, range 4.9-24.7 hours) was -246 mm3 (-3.3%, p = 0.05) and orbital volume change was +248 mm3 (+2.2%, p = 0.24). Dividing the study population into groups based on mannitol dose did not yield any statistically significant change. Conclusions: Human globe volume decreases after intravenous mannitol administration, while orbital volume increases. These volume changes occur during the time period when intraocular pressure normalizes, after the pressure-lowering effects of the drug. This novel volumetric information improves our understanding of mannitol’s mechanism of action and its effects on human ocular and periocular tissues.