We searched for the presence of apoptotic cell death and studied the distribution of bcl-2, an oncoprotein that counteracts apoptosis, in amyotrophic lateral sclerosis (ALS). Brain and spinal cord specimens from 12 ALS patients were compared with those from six non-neurological controls. ALS brain tissue was pre-selected by the presence of reactive cortical damage. Apoptosis was demonstrated by in situ end-labelling of fragmented DNA, a method that is suitable for formalin-fixed, paraffin-embedded tissue. All ALS patients exhibited some apoptosis, eight of them did so in each of the three central nervous system (CNS)-levels studied. Apoptosis was not restricted to the motor system, but also affected other neuronal and non-neuronal CNS elements. Apoptosis corresponded with cell shrinkage, and neuronophagia in Nissl stains and with small Nissl-positive bodies. None of the non-neurological controls showed as much apoptosis as any of the ALS cases. Immunocytochemically, the overall distribution of Bcl-2 did not differ between ALS and non-neurological controls. In ALS, however, we found variable degrees of increased Bcl-2 expressed in the nuclei and in the cytoplasm. We found no inverse relationship between apoptosis and bcl-2 expression.