Purpose: To present data on clinical response to eplerenone over a 1-year period in patients with central serous chorioretinopathy (CSC), and to evaluate optical coherence tomography (OCT) variables as predictors of treatment response at 3- and 12-month follow-up visits. Methods: Patients with acute or chronic CSC treated with eplerenone were retrospectively included. Clinical and imaging characteristics were recorded at baseline and at the 3-month and 12-month follow-up visits. Changes from baseline in quantitative measurements were calculated at each follow-up. Logistic regression analysis was computed to correlate clinical and OCT parameters at baseline with response to treatment at 3 and 12 months of follow-up. Results: A total of 50 eyes of 50 patients were included in the study. Mean ± SD best corrected visual acuity (BCVA) was 0.20 ± 0.14 Logarithm of the Minimum Angle of Resolution (LogMAR) at baseline and significantly improved at both the 3-month (0.12 ± 0.13 LogMAR, p < 0.0001) and 12-month (0.10 ± 0.12 LogMAR, p < 0.0001) follow-up visits. At the 3-month follow-up visit, 25 out of 50 eyes (50.0%) demonstrated macular complete subretinal fluid (SRF) resolution, while 13 eyes (26.0%) showed macular partial SRF resolution, and 12 eyes (24%) had neither partial nor complete macular SRF resolution. Among those patients with macular partial or complete SRF resolution at 3 months and thus not shifted to photodynamic therapy, 36 out of 38 cases had macular complete SRF resolution at the 12-month follow-up visit. There was a significant change from baseline at both follow-up visits in all anatomical OCT parameters (except for reduction in choroidal thickness that did not reach the statistical significance at the 12-month follow-up visit). Several OCT parameters at baseline were independently significant predictors for macular subretinal fluid complete resolution at 3 months, including (i) a thicker subfoveal choroidal thickness; (ii) a smaller subretinal fluid maximum diameter; (iii) a lower number of serous pigment epithelium detachments; and (iv) a lower number of intraretinal hyperreflective foci. Conclusion: Treatment with eplerenone in CSC patients is confirmed to be beneficial for both anatomical and functional outcomes. We identified attractive OCT metrics that could potentially be used as a tool to select patients who might mainly benefit from this treatment.