Age-related macular degeneration (AMD) is the leading cause of blindness worldwide. AMD is characterized by the deposition of drusen aggregates under the retinal pigment epithelium (RPE). Clusterin/apo J, a multifunctional secreted chaperone, is one of the major proteins accumulating in drusen deposits. The regulation of clusterin expression is not well characterized but the promoter of clusterin contains a CpG-rich methylation domain. Since aging affects both DNA methylation and histone acetylation status, the epigenetic regulation might have an important role in clusterin/apo J expression. Our purpose was to elucidate whether the induction of DNA hypomethylation with 5-aza-2'-deoxycytidine (AZA) and histone hyperacetylation with trichostatin A (TSA) could affect the clusterin transcription, protein levels, and secretion in retinal pigment epithelial cells. We observed that both TSA and AZA treatments induced a prominent increase in the expression levels of clusterin mRNA and protein in ARPE-19 cells, as well as in the secretion of clusterin protein. Furthermore, valproic acid, an antiepileptic drug and a recently identified inhibitor of histone deacetylases (HDAC), induced a significant increase in clusterin protein expression and secretion in retinal pigment epithelial cells. HDAC inhibitors are characterized as inhibitors of angiogenesis, and clusterin as a complement inhibitor. Our results indicate that epigenetic factors regulate the clusterin expression of RPE cells and thus might affect the pathogenesis of AMD via the inhibition of angiogenesis and inflammation.