The involvement of extracelluar Ca in experimental muscle damage has been studied in an isolated mouse soleus muscle preparation. The enzyme efflux and ultrastructural damage seen after excessive contractile activity were markedly reduced when the extracellular Ca was withdrawn. Low extracellular Ca also protected against the large enzyme efflux seen after treatment with low concentrations of detergent. Treatment of the muscle with the Ca ionophore A23187 caused significant release of enzyme from the muscle. Nifedipine did not prevent the enzyme release after stimulation, and although in some circumstances verapamil appeared to have some protective effect this was probably due to a local anesthetic action on the muscle and not to any specific effect on Ca movement. Extracellular Ca is important in mediating at least the 2 forms of muscle damage studied here.