Following contusive spinal cord injury (SCI), calpain activity is dramatically increased and remains elevated for days to weeks. Although calpain inhibition has previously been demonstrated to be neuroprotective following spinal cord injury, most studies administered the calpain inhibitor at a single time point. We hypothesized that sustained calpain inhibition would improve functional and pathological outcomes, as compared to the results obtained with a single postinjury administration of the calpain inhibitor. Contusion SCI was produced in female Long-Evans rats using the Infinite Horizon spinal cord injury impactor at the 200 kdyn force setting. Open-field locomotor function was evaluated until 6 weeks postinjury. Histological assessment of lesion volume and tissue sparing was performed at 6 weeks after SCI. Calpain inhibitor MDL28170 administered as a single postinjury i.v. bolus (20 mg/kg) or as a daily i.p. dose (1 mg/kg) improved locomotor function, but did not increase tissue sparing. Combined i.v. and daily i.p. MDL28170 administration resulted in significant improvement in both functional and pathological outcome measures, supporting the calpain theory of SCI proposed by Dr. Banik and colleagues.