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PURPOSE To compare the anatomic results of optical coherence tomography angiography (OCTA)-guided half-dose photodynamic therapy (PDT) versus indocyanine green angiography (ICGA)-guided PDT in eyes with acute central serous chorioretinopathy. METHODS This study is a prospective, single-center, noninferiority, double-masked, randomized, controlled clinical trial. Fifty-one eyes of 45 patients with acute central serous chorioretinopathy were recruited, and randomized to an ICGA-guided group and an OCTA-guided group. The primary outcome measures were the rates of complete subretinal fluid (SRF) resolution at 1 month and 3 months. RESULTS Forty-six eyes of 40 patients finished the follow-up and were analyzed. In the OCTA-guided group, the SRF was completely resolved in 13 (56.5%) eyes within 1 month and in 21 (91.3%) eyes within 3 months. In the ICGA-guided group, the SRF was resolved in 16 (69.6%) of the eyes within 1 month and in 22 (95.7%) of the eyes by 3 months. Optical coherence tomography angiography-guided PDT was demonstrated noninferior to ICGA-guided PDT for SRF resolution rate at 3 months (P = 0.016), but not at 1 month (P = 0.311) for acute central serous chorioretinopathy patients. Subretinal fluid did not recur in any of the eyes in the OCTA-guided group, but did recur in 2 eyes (8.7%) of the ICGA-guided group during the 3-month follow-up period. CONCLUSION Optical coherence tomography angiography-guided PDT seemed to be noninferior to ICGA-guided PDT for resolution of SRF at 3 months in eyes with acute central serous chorioretinopathy.