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Purpose: To evaluate the effect of spironolactone on chronic central serous chorioretinopathy (CSC). Methods: In this prospective interventional case series, patients with chronic cSc were treated with spironolactone (25 mg daily) for at least 6 weeks. If the subretinal fluid (SRF) had not completely resolved by this time, treatment was continued, and the dosage was increased to 25 mg twice daily. Primary outcome measure was the change in maximum SRF height at the final follow-up visit, as detected by optical coherence tomography. Secondary outcome measures were changes in best corrected visual acuity (BCVA) and central macular thickness (CMT). Results: Sixteen eyes of 14 patients with chronic cSc were enrolled. Mean follow-up time was 6.4 ± 4.3 months. Baseline BcVA was 0.54 ± 0.44 logarithm of the minimum angle of resolution (log MAR), which improved to 0.42 ± 0.43 log MAR at the final visit (P = 0.04). Mean cMT decreased from 282.69 ± 103.23 μm at baseline to 236.75 ± 90.10 μm at final visit (P = 0.11), and the mean of maximum SRF height decreased from 155.63 ± 95.27 μm at baseline to 77.19 ± 95.68 μm at the final visit (P = 0.04). SRF resolved completely in seven eyes (43.75%). Conclusion: In eyes with persistent SRF due to CSC, spironolactone therapy was associated with a statistically significant decrease in maximum SRF height, as well as an improvement in BCVA.