The effect of natural phenol derivatives was studied on skeletal type sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. The majority of the tested derivatives exerted inhibitory effect on the Ca2+-ATPase with an ascending sequence in regard to their effectiveness (IC50): cineole (3.33 mM) < ortho-vanillin (IC50=1.13 mM) < 4-methyl-2-nitrophenol (1104 μM) < vanillin (525 μM) < thymol (224 μM) < carvacrol (162 μM). In two cases biphasic characteristic was observed: trans-anethole and meta-anisaldehyde first caused activation followed by inhibition (with IC50-s of 141 and 1903 μM respectively) as their concentration was increased. In some cases (cineole, ortho-vanillin,meta-anisaldehyde) total inhibition of Ca2+-ATPase could not be reached as the result of the limited solubility of these drugs.Para-anisaldehyde and 6-amino-meta-cresol did not show any effect up to 3 mM. In Ca2+ release experiments drugs were applied on heavy sarcoplasmic reticulum vesicles isolated from skeletal muscle and actively loaded with calcium. Only thymol and carvacrol were able to evoke Ca2+ release with EC50 values of 158 ± 16 and 211 ± 55 μM respectively. Futhermore the effect of thymol and carvacrol was tested on the isolated ryanodine receptor incorporated into artificial lipid bilayer. Both drugs activated the RyR when applied in concentrations identical to their EC50 values. These observations show that small differences in the structure of phenol derivatives sometimes have little impact on their effect on the sarcoplasmic reticulum Ca2+-ATPase or ryanodine receptor (thymol and carvacrol) whereas in certain cases they can completely abolish a particular effect (para- andmeta-anysaldehide).