Background/objectives: To prospectively evaluate changes in peripapillary retinal nerve fibre layer (pRNFL), in all macular layers and in choroidal thickness (CT) in a cohort of systemic lupus erythematosus (SLE) patients without ophthalmologic manifestations. To associate those changes with ophthalmic characteristics, disease activity state, medication and systemic comorbidities. Subjects/methods: Prospective cohort study of 68 previously diagnosed SLE patients. In two study visits (V1 and V2) at least 12 months apart, patients underwent a complete ophthalmologic examination including spectral domain-optical coherence tomography (SD-OCT) and an autoimmune disease specialist assessment. Automatic retinal segmentation was performed. pRNFL was determined globally and in the six peripapillary sectors and each macular layer thickness was determined in the nine early treatment diabetic retinopathy study (ETDRS) subfields. CT was manually measured at 13 locations in the posterior pole. Only one eye per patient was randomly selected for inclusion. Generalised linear mixed effects models were employed. Results: Sixty-five patients completed the study. The median follow-up time was twelve months. At V2, pRNFL was significantly thinner globally (p = 0.006) and in the temporal inferior sector (p = 0.017). Patients under chronic medication with anticoagulants or antihypertensives had significantly thinner pRNFL in some locations. No significant changes were observed in macular layers or choroidal thickness between study visits. Conclusions: SLE patients presented early SD-OCT signs of neurodegeneration, evidenced by a progressive reduction in pRNFL thickness. Regardless of study visit, baseline chronic medication with anticoagulants or antihypertensives was associated with lower pRNFL thickness, accounting for a deleterious effect of cardiovascular risk factors.