Transgenic mice with several copies of a mutated human superoxide dismutase 1 (Gly93-Ala substitution) gene, i.e. a mutation responsible for the development of familial amyotrophic lateral sclerosis (ALS), integrated into the mouse genome, develop a slowly progressive paralysis of the hind-limbs accompanied by a corresponding degeneration of spinal cord neuronal tissue. We have used two different lines of these transgenic mice [a low (approximately 12 copies) or a high (approximately 24) copy number of the mutated human superoxide dismutase 1 gene] to find evidence of programmed cell death in affected spinal cord tissue at distinct age groups. Hallmarks of programmed cell death, i.e. DNA laddering and an increase in caspase 3-like activity, were found in the spinal cord of both lines of mice. Behavioural evaluation of the mice indicated that the hallmarks of programmed cell death were mainly, but not exclusively found in symptomatic animals just before or at end-stage. These data suggest that programmed cell death may play a role in the disease process of familial ALS particularly in its terminal phase.