Introduction:As part of cancer research, mycotherapy is a relatively new and promissory source of agents with immunomodulating and antitumor properties. Ongoing research projects are aiming to provide mushrooms as a new generation of "biotherapeutics". In addition to high-molecular weight polysaccharides, efforts should be made to find new anticancer drugs using low-molecular weight secondary metabolites, e.g. phenolic compounds that can inhibit or trigger specific biochemical signals leading to cancer. Methods: An in silico approach based on the structural similarity of low-molecular weight mycocompounds (phenolics) with respect to antitumor substances and molecules with modulatory effects on epigenetic events was used. For the screening of mushroom molecules with potential regulatory effects on epigenome (obtained on Web of Science, August 2015), the enzymes histone acetyltransferase (HAT), histone deacetylase (HDAC) and DNA methyltransferase (DNMT) were chosen as targets. Similarity analysis were performed with the software Saranea. Moreover, the determination of the chemical structural similitude between phenolic compounds of Pleurotus ostreatus (oyster mushroom) and antitumor reference compounds was carried out with the software Power MV 0.61. Tanimoto's coefficients (Tc) similar or higher to 0.90 were considered as significant. Results: Seven mushroom compounds with high structural similarity to reference substances with modulatory activity on epigenetic events (Tc ≥0.90) were identified: 5 with a potential effect on histone acetylation/deacetylation, and 3 acting on the enzyme DNMT. Twenty antitumor reference compounds showed structural similarity to 3 phenols occurring in P. ostreatus, corresponding the largest number to protocatechuic acid and the flavonoids myricetin and naringin. According to its similarity to the antitumor compounds, they would act as DNA antimetabolites, antimitotic, and/or alkylating agents. Conclusion: It seems feasible to harness the natural pool of mushrooms secondary metabolites and to predict by in silico approaches their potential modulatory effects on epigenetic events and antitumor activity, in special phenolics occurring in P. ostreatus. This is an exciting advance for developing nutraceuticals/ cosmeceuticals and innovative drugs.