Brain edema accounts for significant morbidity and mortality in many neurologic conditions such as head trauma, stroke, meningitis, and brain tumor. The water channel aquaporin-4 (AQP4) has been found to be an important determinant of brain water accumulation and clearance of excess brain water. We report the development of a noninvasive near-infrared (NIR) light-scattering method to compare the early kinetics of brain swelling in normal and AQP4-deficient mice. Brain tissue was illuminated through the intact skull with NIR light at 850 nm, and steady-state scattered light intensity was monitored at an angle of 90 degrees at a position on the skull ∼10 mm from the illuminated site. NIR light scattering reversibly increased with brain swelling (ΔI/Io ∼25% per 1% increase in brain water content), but was insensitive to changes in cerebral blood flow, blood oxygenation, or blood flow-related changes in intracranial pressure (ICP). ΔI/Io increased approximately linearly with brain water content as measured by wet-to-dry weight ratios. Acute water intoxication (intraperitoneal water, 20% body weight) produced a gradual increase in ΔI/Io of 12 ± 4% in wild-type mice at 5 min, much greater than that of 2 ± 1% in AQP4-null mice. Correlation of the NIR signal with ICP showed that increased ΔI/Io preceded measurable increases in ICP, indicating the ability of the NIR method to detect early brain edema before ICP elevation. NIR light scattering provides a simple noninvasive method to monitor brain edema in mice, with potential clinical applications. © 2005 Wiley-Liss, Inc.