Objectives <p>To identify the specific predictors of treatment response to subthreshold micropulse laser (SML) and oral spironolactone therapy in patients with central serous chorioretinopathy (CSC).</p> Methods <p>Patients diagnosed with CSC and treated with SML or spironolactone were included in this cohort study. Baseline characteristics, systemic factors, and various imaging characteristics were included as potential predictors of treatment response. Univariate and multivariate analysis was performed to identify predictive factors for the disease.</p> Results <p>A total of 103 eyes from 97 patients were included and divided into SML group (52 eyes) and spironolactone group (51 eyes). SRF resolution and OCT parameters, including CRT (<i>p</i> = 0.018) and SRF height (<i>p</i> &lt; 0.001), decreased significantly in both groups, but SFCT decreased only in the spironolactone group. Regression analysis revealed that baseline SRF area was correlated with disease resolution in both SML (<i>p</i> = 0.005) and spironolactone (<i>p</i> = 0.016) groups, whereas changes in CRT and SFCT were correlated with a history of hyperuricemia (<i>p</i> = 0.047) and drinking (<i>p</i> = 0.035) only in the spironolactone group.</p> Conclusion <p>Both SML and oral spironolactone are alternative therapies with similar efficacy. The SRF area at baseline can be a predictor of disease resolution. A history of hyperuricemia and drinking correlates with worse efficacy with spironolactone treatment.</p> Trial registration <p>The study was registered on Chinese Clinical Trial Registry (identifier: ChiCTR2100044356) at 17 March 2021.</p>