We analyzed the effect of HMG-CoA reductase inhibitors on Ca²⁺ release from the sarcoplasmic reticulum (SR) using chemically skinned skeletal muscle fibers from the mouse and the rat. Cerivastatin (>20 μM) released Ca²⁺ from the SR, while pravastatin showed only a little effect. The rates of Ca²⁺ release were increased by cerivastatin at all Ca²⁺ concentrations tested. Cerivastatin-induced Ca²⁺ release in the presence of Ca²⁺ was affected by adenosine monophosphate, Mg²⁺, and procaine in essentially the same way as for caffeine-induced Ca²⁺ release. The Ca²⁺-uptake capacity of the SR was reduced after co-treatment with ryanodine and cerivastatin at pCa 6.0 to a much greater extent than with ryanodine alone. Thus, cerivastatin-induced Ca²⁺ release in the presence of Ca²⁺ must be a result of the activation of the Ca²⁺-induced Ca²⁺ release (CICR) mechanism of the ryanodine receptor. However, even when CICR was maximally inhibited by Mg²⁺ and procaine, or in the practical absence of Ca²⁺ (pCa >8), cerivastatin still caused Ca²⁺ release. These results indicate that cerivastatin causes Ca²⁺ release also by activating some other mechanism(s) in addition to the activation of CICR. Either or both of these effects might be related to its adverse effect, rhabdomyolysis.