Oxidative stress plays a pivotal role in ischemic injury and p66ShcA-ko mice exhibit both lower oxidative stress and decreased tissue damage following hindlimb ischemia. Thus, it was investigated whether tissue regeneration following acute hindlimb ischemia was altered in p66ShcA-ko mice. Upon femoral artery dissection, muscle regeneration started earlier and was completed faster than in wt control. Moreover, faster regeneration was associated to decreased oxidative stress. Unlike ischemia, cardiotoxin injury induced similar skeletal muscle damage in both genotypes. However, p66ShcA-ko mice regenerated faster, in agreement with the regenerative advantage upon ischemia. Since no difference between p66ShcA-wt and ko mice was found in blood perfusion recovery after ischemia, Satellite Cells (SCs), a resident population of myogenic progenitors, were examined. Similar SCs numbers were present in wt and ko mice. However, in vitro cultured p66ShcA-ko SCs displayed lower oxidative stress levels, higher proliferation rate and differentiated faster than wt. Furthermore, when exposed to sublethal H2O2 doses, p66ShcA-ko SCs were resistant to H2O2-induced inhibition of differentiation. Finally, myogenic conversion induced by MyoD overexpression was more efficient in p66ShcA-ko fibroblasts compared to wt. The present work demonstrates that oxidative stress and p66ShcA play a crucial role in the regenerative pathways activated by acute ischemia.