To assess optical coherence tomography in differentiating optic disc edema (ODE) due to papilledema and other optic neuropathies from optic nerve head drusen (ONHD). Methods: Optical coherence tomographic images from 60 subjects (20 with ODE, 20 with ONHD, and 20 control subjects) were assessed qualitatively and quantitatively. Qualitative criteria for ODE included an elevated optic nerve head with smooth internal contour and subretinal hyporeflective space (SHYPS) with recumbent "lazy V" pattern. Optic nerve head drusen displayed a "lumpybumpy" internal optic nerve contour and a rapid decline in SHYPS thickness. Quantitative comparisons included retinal nerve fiber layer and SHYPS thickness. Results: Optical coherence tomography differentiated ODE from ONHD qualitatively (sensitivity, 63%; speci-ficity, 63%) and quantitatively (sensitivity, 80%; specificity, 90%). Respective differences in mean retinal nerve fiber layer thickness between ODE and ONHD were significant (P Ͻ .002) superiorly (206.8 vs 121.7 µm), nasally (176.3 vs 78.6 µm), inferiorly (247.2 vs 153.8 µm), and temporally (180.0 vs 85.5 µm). Respective differences in mean SHYPS thickness between ODE and ONHD were significant (PϽ .001) at radii of 0.75 mm (512.1 vs 274.4 µm), 1.5 mm (291.4 vs 103.0 µm), and 2.0 mm (145.5 vs 60.7 µm). Conclusion: Optical coherence tomography can differentiate ODE from ONHD, particularly when the nasal retinal nerve fiber layer and SHYPS thickness at the 2.0-mm radius are greater than 86 µm and 127 µm, respectively.