Purpose: 7-ketocholesterol (7kCh), a natural byproduct of oxidation in lipoprotein deposits is implicated in the pathogenesis of diabetic retinopathy and age-related macular degeneration (AMD). This study was performed to investigate whether several clinical drugs can inhibit 7kCh-induced caspase activation and mitigate its apoptotic effects on RETINAL cells in vitro. Method: Two populations of RETINAL cells, human RETINAL pigment epithelial cells (ARPE-19) and rat neuroRETINAL cells (R28) were exposed to 7kCh in the presence of the following inhibitors: Z-VAD-FMK (pan-caspase inhibitor), simvastatin, memantine, epicatechin, and Z-IETD-FMK (caspase-8 inhibitor) or Z-ATAD-FMK (caspase-12 inhibitor). Caspase-3/7,-8, and-12 activity levels were measured by fluorochrome caspase assays to quantify cell death. IncuCyte live-cell microscopic images were obtained to quantify cell counts. Results: Exposure to 7kCh for 24 hours significantly increased caspase activities for both ARPE-19 and R28 cells (P < 0. 05). In ARPE cells, pretreatment with various drugs had significantly lower caspase-3/7,-8, and-12 activities, reported in % change in mean signal intensity (msi): Z-VAD-FMK (48% decrease, P < 0. 01), memantine (decreased 47. 8% at 1 µ M, P = 0. 0039 and 81. 9% at 1 mM, P < 0. 001), simvastatin (decreased 85. 3% at 0. 01 µ M, P < 0. 001 and 84. 8% at 0. 05 µ M, P < 0. 001) or epicatechin (83. 6% decrease, P < 0. 05), Z-IETD-FMK (68. 1% decrease, P < 0. 01), and Z-ATAD-FMK (47. 7% decrease, P = 0. 0017). In contrast, R28 cells exposed to 7kCh continued to have elevated caspase3/7,-8, and-12 activities (between 25. 7% decrease and 17. 5% increase in msi, P > 0. 05) regardless of the pretreatment. Conclusion: Several current drugs protect ARPE-19 cells but not R28 cells from 7kChinduced apoptosis, suggesting that a multiple-drug approach is needed to protect both cells types in various RETINAL diseases.