While multiple molecular mechanisms contribute to midbrain nigrostriatal dopaminergic degeneration in Parkinson’s disease (PD), the mechanism of damage in non-dopaminergic sites within the central nervous system, including the spinal cord, is not well understood. Thus, in order to understand the comprehensive pathophysiology underlying this devastating disease, postmortem spinal cord tissue samples (cervical, thoracic and lumbar segments) from patients with PD were analyzed compared to age-matched normal subjects or Alzheimer’s disease (AD) for selective molecular markers of neurodegeneration and inflammation. Distal axonal degeneration, relative abundance of both sensory and motor neuron death, selective loss of ChAT+ motoneurons, reactive astrogliosis, microgliosis, increased cycloxygenase-2 (Cox-2) expression, and infiltration of T cells were observed in spinal cords of PD patients compared to normal subjects. Biochemical analyses of spinal cord tissues revealed associated inflammatory and proteolytic events (elevated levels of Cox-2, expression and activity of μ- and m-calpain, degradation of axonal neurofilament protein, and concomitantly low levels of endogenous inhibitor – calpastatin) in spinal cords of PD patients. Thus, pathologically upregulated calpain activity in spinal cords of patients with PD may contribute to inflammatory response-mediated neuronal death, leading to motor dysfunction.