Heat shock protein expression is elevated upon exposure to a variety of stresses and limits the extent of the stress-induced damage. In order to investigate the putative role of inducible 70kDa heat shock protein (HSP70) in skeletal muscle damage and regeneration, soleus and tibialis anterior (TA) muscles from HSP70 overexpressing transgenic mice were cryolesioned and analyzed after 1, 10 and 21 days. Histological analysis showed that the muscles from both HSP70 mice and wild type mice treated with radicicol (HSP inducer) had decreased necrosis after cryolesion when compared to controls. The decrease in muscle fiber cross-section area (CSA) in both soleus and TA muscles in 10 days post lesion was attenuated in HSP70 mice when compared to wild type mice. Glutathione peroxidase (GPx) activity was increased at 1 day after cryolesion in both HSP70 and control mice and remained elevated up to 21 days. Immunodetection of neuronal cell adhesion molecule (NCAM, a satellite cell marker) and developmental/neonatal MHC (d/n) were significantly lower in cryolesioned HSP70 mice as compared to cryolesioned controls. These results suggest that HSP70 protects skeletal muscle against injury and radicicol might be useful as a skeletal muscle protective agent.