Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss and astrogliosis. We studied the immunohistochemical expression of S-100beta, a calcium-binding protein with both neurotrophic and neurotoxic activities, in the spinal cord of patients with ALS. Adjacent sections were processed with an in situ end-labeling technique for the demonstration of apoptosis-related DNA fragmentation. In controls, low expression of S-100beta was found in astrocytes but not motor neurons. Compared to controls, S-100beta was overexpressed in ALS. Most stained cells were reactive astrocytes, but a minority of motor neurons was also labeled. Neuronal labeling was unrelated to the presence of signs of atrophy/degeneration. S-100beta expression was also unrelated to neuronal or glial apoptosis. S-100beta upregulation in ALS spinal cord suggests that the protein might be involved in cellular defense mechanisms against oxidative stress.