PURPOSE: To evaluate spectral-domain optical coherence tomography (SD-OCT) in providing reliable and reproducible parameters for grading geographic atrophy (GA) compared with fundus autofluorescence (FAF) images acquired by confocal scanning laser ophthalmoscopy (cSLO). DESIGN: Prospective observational study. PARTICIPANTS: A total of 81 eyes of 42 patients with GA. METHODS: Patients with atrophic age-related macular degeneration (AMD) were enrolled on the basis of total GA lesion size ranging from 0.5 to 7 disc areas and best-corrected visual acuity of at least 20/200. A novel combined cSLO-SD-OCT system (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany) was used to grade foveal involvement and to manually measure disease extent at the level of the outer neurosensory layers and retinal pigment epithelium (RPE) at the site of GA lesions. Two readers of the Vienna Reading Center graded all obtained volume stacks (20×20 degrees), and the results were correlated to FAF. MAIN OUTCOME MEASURES: Choroidal signal enhancements and alterations of the RPE, external limiting membrane (ELM), and outer plexiform layer by SD-OCT. These parameters were compared with the lesion measured with severely decreased FAF. RESULTS: Foveal involvement or sparing was definitely identified in 75 of 81 eyes based on SD-OCT by both graders (inter-grader agreement: κ=0.6, P < 0.01). In FAF, inter-grader agreement regarding foveal involvement was lower (48/81 eyes, inter-grader agreement: κ=0.3, P < 0.01). Severely decreased FAF was measured over a mean area of 8.97 mm(2) for grader 1 (G1) and 9.54 mm(2) for grader 2 (G2), consistent with the mean SD-OCT quantification of the sub-RPE choroidal signal enhancement (8.9 mm(2) [G1] -9.4 mm(2) [G2]) and ELM loss with 8.7 mm(2) (G1) -10.2 mm(2) (G2). In contrast, complete morphologic absence of the RPE layer by SD-OCT was significantly smaller than the GA size in FAF (R(2)=0.400). Inter-reader agreement was highest regarding complete choroidal signal enhancement (0.98) and ELM loss (0.98). CONCLUSIONS: Absence of FAF in GA lesions is consistent with morphologic RPE loss or advanced RPE disruption and is associated with alterations of the outer retinal layers as identified by SD-OCT. Lesion size is precisely determinable by SD-OCT, and foveal involvement is more accurate by SD-OCT than by FAF.