Objectives <p>Vascular endothelial growth factor A (VEGFA) plays a critical role in the pathogenesis of diabetic macular edema (DME) in patients with type 2 diabetes mellitus (T2DM). Herein, we sought to determine whether palmitoylation modulates the stability and function of VEGFA in the context of DME.</p> Methods <p>VEGFA protein levels were measured by western blotting in retinal pigment epithelial (RPE) tissues from mice and in cultured RPE cell lines. Palmitoylation of VEGFA was assessed using acyl‑biotin exchange (ABE) and Click‑iT pulldown assays. Cell proliferation was evaluated with the Cell Counting Kit‑8 (CCK‑8) assay. The interaction between VEGFA and zinc finger DHHC-type containing 19 (ZDHHC19) was examined by co‑immunoprecipitation. Retinal histopathology in DME mice was evaluated by hematoxylin‑eosin (H&amp;E) staining.</p> Results <p>VEGFA levels were elevated in the RPE of DME mice compared with those of T2DM mice. Pharmacological inhibition of palmitoylation with 2‑bromopalmitate (2‑BP) reduced VEGFA protein expression in cultured cells. ZDHHC19 was identified as the palmitoyltransferase responsible for VEGFA. Wild‑type ZDHHC19 failed to palmitoylate the VEGFA‑C387A mutant, and the catalytically inactive ZDHHC19‑C142S mutant also lacked activity toward VEGFA. Overexpression of wild‑type VEGFA or ZDHHC19 significantly promoted RPE cell proliferation, whereas the VEGFA‑C387A and ZDHHC19‑C142S mutants had no effect. Consistent with these in vitro findings, wild‑type VEGFA or ZDHHC19 overexpression exacerbated DME development in mice, while the corresponding mutants did not significantly affect disease progression.</p> Conclusion <p>ZDHHC19‑mediated palmitoylation of VEGFA contributes to DME pathogenesis and may serve as a potential therapeutic target and biomarker for this disease.</p>