Proliferative vitreoretinopathy (PVR) is characterized by the proliferation and migration of retinal pigment epithelial (RPE) cells in the vitreous cavity. The drug hypericin, which is already in clinical use as an antidepressant, has shown promise as an antiviral and antineoplastic agent. To investigate the therapeutic potential of hypericin in PVR, we incubated RPE cells in standard medium with various serum concentrations containing 0.5 to 5μM hypericin. In some experiments we studied the effects of hypericin in conjunction with the RPE growth stimulating cytokine tumor necrosis factor alpha (TNF-α). Dose-dependent inhibition of RPE cell proliferation with IC50values of 0.7μM and 3.3μM in 1% and 5% serum respectively, was found. Even in conjunction with TNF-α, hypericin inhibited RPE proliferation with an IC50value of 1.5μM. The drug inhibited PKC activity in cells treated with a 2.5μM dose by 72% after 30 min and by 100% after 180 min. Finally, hypericin induced RPE cells to undergo apoptotic cell death, as shown by the presence of DNA laddering. These results suggest that hypericin may have potential as a therapeutic drug for PVR and that its antiproliferative and apoptotic effects on RPE cellsin vitroare in part mediated by PKC.