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Purpose: Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy., Material and Methods: This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®)., Results: Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42-191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22-217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88-218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures., Conclusion: Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.