PURPOSE To evaluate differences between the retinal nerve fiber layer (RNFL) thickness and RNFL + ganglion cell layer (GCL) thickness in patients affected by Alzheimer's disease (AD) and healthy patients using spectral-domain optical coherence tomography (SD-OCT). METHODS This was a case-control prospective study. Twenty-one AD patients and 21 healthy subjects underwent neurological examination, clock-drawing test (CDT), Mini Mental State Examination (MMSE), and comprehensive ophthalmic evaluation with visual acuity. SD-OCT examination was performed using Spectralis and RTVue-100. An RNFL thickness map was obtained using the Spectralis volume protocol with 19 lines on the 30° field centered on the macula. On each B-scan, the outer RNFL limit was manually set. Statistical analysis was performed to assess interoperator RNFL evaluation thickness. An RNFL+GCL thickness map was obtained using the RTVue-100 MM6 protocol. Maps were divided into the nine ETDRS subfields and each map value in every area was evaluated. A single eye from each patient was randomly chosen to perform the analysis. Differences between AD and healthy subjects were assessed. RESULTS The two study groups were age and sex matched. MMSE results were 19.9 ± 3.1 and 27.9 ± 1.3, respectively (P < 0.001). There was good agreement in the manual delimitation of the RNFL layer. There was a significant difference in the thickness of both the RNFL and the RNFL+GCL in all examined fields. For example, in the inferior internal subfield, the RNFL thickness was 28.1 ± 3.1 μm for AD patients and 32.6 ± 3.8 μm for healthy subjects (P < 0.001). CONCLUSIONS These results indicate that RNFL and RNFL+GCL thickness measurements are reduced in AD patients compared with healthy subjects. This finding may represent a useful element for the diagnosis and follow-up of this pathology.