PURPOSE: The aim of this study was to evaluate the association between prostacyclin analog (PCA) therapy and the long-term incidence of diabetic retinopathy (DR) in patients with diabetes and pulmonary arterial hypertension. METHODS: In this retrospective, real-world cohort study, the authors used 1:1 propensity score matching within the TriNetX Global Collaborative Network to compare patients receiving dual therapy including PCAs versus matched controls treated with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, or soluble guanylate cyclase stimulators without PCAs. Patients with a prior DR diagnosis were excluded. The incidence of nonproliferative DR, proliferative DR, and diabetes with ophthalmic complications was assessed over a 5-year period using Cox proportional hazards models and Kaplan-Meier survival analyses. RESULTS: Among 2,584 matched patients in both cohorts, PCA therapy was associated with a significantly lower incidence of nonproliferative DR (24 vs. 42 events; hazard ratio [HR] = 0.59; 95% confidence interval [CI], 0.35-0.97; P = 0.0345) and diabetes with ophthalmic complications (65 vs. 99 events; HR = 0.67; 95% CI, 0.49-0.91; P = 0.0105). No statistically significant difference was observed in proliferative DR incidence (10 vs. 15 events; HR = 0.63; 95% CI, 0.27-1.43; P = 0.2617). CONCLUSION: PCA therapy may be associated with a reduced risk of developing DR, suggesting potential systemic microvascular protective effects. Further prospective studies are warranted to explore the therapeutic role of PCAs in diabetes-related retinal disease.