AIM: To describe the influence of adding topical nepafenac to both; oral eplerenone and intravitreal aflibercept on serous foveal detachment in eyes with central serous chorioretinopathy (CSCR). METHODS: This retrospective cohort study included 31 eyes with non-resolving and recurrent CSCR that have been treated between 2015 and 2022 at Kasr Alainy Hospital. They were subdivided into Group A, which had been treated with a combination of systemic eplerenone, intravitreal aflibercept and topical nepafenac, and Group B, which had been treated with a combination of systemic eplerenone and intravitreal aflibercept (without topical nepafenac). Our outcome measures included changes in the best corrected visual acuity (BCVA), central subfield macular thickness (CMT) and serous detachment height (SDH) at baseline and at 2mo after treatment. RESULTS: Group A included 16 eyes. BCVA improved significantly from a logMAR of 0.62±0.44 to 0.42±0.47 (P=0.03), CMT decreased significantly from 401±61 to 301±100 µm, and SDH decreased significantly from 188±81 to 71±100 µm. Group B included 15 eyes. BCVA improved significantly from a logMAR of 0.68±0.39 to 0.55±0.62 (P=0.03), CMT decreased significantly from 411±39 µm to 334±92 µm, and SDH decreased significantly from 191±88 to 121±74 µm. There was a significant difference between changes in BCVA, CMT, and SDH between the two groups. CONCLUSION: Using topical nepafenac in combination with both systemic eplerenone, and intravitreal aflibercept may provide better results in the treatment of CSCR.