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Compared to plants, nowadays mushrooms attract more attention as functional foods, due to a number of advantages in manipulating them. This study aimed to screen the chemical composition (fatty acids and phenolics) and antioxidant potential (OH&#8226;, 2,2-diphenyl-1-picrylhydrazyl (DPPH&#8226;) and ferric reducing ability of plasma (FRAP)) of two edible mushrooms, <i>Coprinus comatus</i> and <i>Coprinellus truncorum,</i> collected from nature and submerged cultivation. Partial least square regression analysis has pointed out the importance of some fatty acids&#8212;more precisely, unsaturated fatty acids (UFAs) followed by fatty acids possessing both short (C6:0 and C8:0) and long (C23:0 and C24:0) saturated chains&#8212;and phenolic compounds (such as protocatechuic acid, daidzein, <i>p</i>-hydroxybenzoic acid, genistein and vanillic acid) for promising anti-OH&#8226;, FRAP and anti-DPPH&#8226; activities, respectively. However, other fatty acids (C16:0, C18:0 and C18:3n3) along with the flavonol isorhamnetin are actually suspected to negatively affect (by acting pro-oxidative) the aforementioned parameters, respectively. Taken together, design of new food supplements targeting oxidative stress might be predominantly based on the various UFAs combinations (C18:2n6, C20:1, C20:2, C20:4n6, C22:2, C22:1n9, etc.), particularly if OH&#8226; is suspected to play an important role.