Background: Bee venom is a promising agent for cancer treatment due to its selective cytotoxic potential for cancer cells through apoptotic pathways. However, there is no evidence for changes in the epigenome and mitochondrial DNA copy numbers after bee venom application. The purpose of this study was to determine the impact of bee venom on cytosine modifications and mi-tochondrial DNA copy number variation. Methods: A broad range of methods was applied to elucidate the impact of bee venom on neoplas-tic cells. These included MTT assay for detection of cytotoxicity, immunostaining of cytosine mod-ifications and mitochondria, assessment of cellular morphology by flow cytometry, and quantifica-tion of mitochondrial DNA copy numbers using QPCR. Results: Bee venom-induced cell death was selective for cancer cells, where it triggered a response characterized by alteration of cytosine modification. In contrast, normal cells were more resistant to DNA modifications. Furthermore, application of the venom resulted in variation of mitochon-drial membrane permeability and mitochondrial DNA copy numbers, together with alterations in cell morphology, manifesting as reduced affected cell size. Conclusion: The study findings suggest that bee venom can be used as a selective DNA (de)methy-lating agent in cancer. Various agents (such as decitabine and 5-azacytidine) have been synthesized and developed for cancer treatment, and a range of syntheses and preparation and application meth-ods have been described for these patented drugs. However, to the best of our knowledge, no previ-ous research has investigated the use of bee venom or any component thereof for epigenetic thera-py in cancer cells.