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Article; Early Access, Objective To conduct an evaluation of the effects of irregular astigmatism on the retinal nerve fiber layer (RNFL) and the retinal layers observed using spectral-domain optical coherence tomography (SD-OCT) in patients who had keratoconus (KC). Materials and Methods A total of 255 eyes from 255 individuals, comprising 72 eyes of KC patients, 70 eyes of patients with astigmia, and 113 eyes of healthy controls were included in the analysis. RNFL scan maps (comprising global, temporal, superotemporal, inferotemporal, nasal, inferonasal, and superonasal maps) and macular thickness (MT) maps of a standard from the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were assessed. The measurements were segmented automatically using Spectralis software, and included the RNFL, inner and outer plexiform layers (IPL, OPL), inner and outer nuclear layers (INL, ONL), ganglion cell layer, retinal pigment epithelium (RPE) in the central 6-mm ETDRS subfield. Results The RNFL thickness in the KC group was lower when compared with the other two groups; however, statistically significant differences were noted in the global, temporal, superotemporal, and inferotemporal sectors (p 0.05 for all). All of the central MT parameters showed significant variation among the groups, while a statistically significant decrease was noted in the KC group, except in the inferior outer sector (p = 0.741). In the segmentation analysis, the KC group had the significantly lowest IPL, ONL, RPE, and outer retinal layer (ORL) thickness among the groups (p 0.05 for each). The astigmatic group was similar to the control group with regard to these parameters (p > 0.05 for each). Conclusion The eyes in the KC group appeared to have a thinner RNFL and MT when compared to those in the astigmatic and control groups. The ORLs, especially the ONL and RPE, were the most affected component of the macula in the KC group.