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Our study assesses the effects of anti-VEGF (Vascular Endothelial Growth Factor) drugs and Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC) activity, on cultured ARPE-19 (Adult Retinal Pigment Epithelial-19) cells that are immortalized human retinal pigment epithelial cells. ARPE-19 cells were treated with the following anti-VEGF drugs: aflibercept, ranibizumab, or bevacizumab at 1× and 2× concentrations of the clinical intravitreal dose (12.5 μL/mL and 25 μL/mL, respectively) and analyzed for transcription profiles of genes associated with the pathogenesis age-related macular degeneration (AMD). HDAC activity was measured using the Fluorometric Histone Deacetylase assay. TSA downregulated <i>HIF-1α</i> and <i>IL-1β</i> genes, and upregulated <i>BCL2L13, CASPASE-9,</i> and <i>IL-18</i> genes. TSA alone or bevacizumab plus TSA showed a significant reduction of HDAC activity compared to untreated ARPE-19 cells. Bevacizumab alone did not significantly alter HDAC activity, but increased gene expression of <i>SOD2, BCL2L13, CASPASE-3,</i> and <i>IL-18</i> and caused downregulation of <i>HIF-1α</i> and <i>IL-18</i>. Combination of bevacizumab plus TSA increased gene expression of <i>SOD2, HIF-1α, GPX3A, BCL2L13,</i> and <i>CASPASE-3</i>, and reduced <i>CASPASE-9</i> and <i>IL-β</i>. In conclusion, we demonstrated that anti-VEGF drugs can: (1) alter expression of genes involved in oxidative stress (<i>GPX3A</i> and <i>SOD2</i>), inflammation (<i>IL-18</i> and <i>IL-1β</i>) and apoptosis (<i>BCL2L13, CASPASE-3,</i> and <i>CASPASE-9</i>), and (2) TSA-induced deacetylation altered transcription for angiogenesis (<i>HIF-1α</i>), apoptosis, and inflammation genes.