Aberrant DNA hypermethylation contributes to myelomagenesis by silencing tumor-suppressor genes. Recently, a few reports have suggested that a novel class of small non-coding RNAs, called Piwi-interacting RNAs (piRNAs), may be involved in the epigenetic regulation of cancer. In this study, for the first time we provided evidence that the expression of piRNA-823 was upregulated in multiple myeloma (MM) patients and cell lines, and positively correlated with clinical stage. Silencing piRNA-823 in MM cells induced deregulation of cell cycle regulators and apoptosis-related proteins expression, accompanied by inhibition of tumorigenicity in vitro and in vivo. Moreover, piRNA-823 was directly relevant to de novo DNA methyltransferases, DNMT3A and 3B, in primary CD138(+) MM cells. The inhibited expression of piRNA-823 in MM cells resulted in marked reduction of DNMT3A and 3B at both mRNA and protein levels, which in turn led to decrease in global DNA methylation and reexpression of methylation-silenced tumor suppressor, p16(INK4A). In addition, piRNA-823 abrogation in MM cells induced reduction of vascular endothelial growth factor secretion, with consequent decreased proangiogenic activity. Altogether, these data support an oncogenic role of piRNA-823 in the biology of MM, providing a rational for the development of piRNA-targeted therapeutic strategies in MM.