It has been suggested that the degeneration of lower motor neurons in amyotrophic lateral sclerosis (ALS) is a transneuronal event, secondary to the loss of corticospinal and corticobulbar neurons. In an attempt to test this hypothesis, the cross-sectional areas of pyramidal cells in layer 5 of the foot and tongue areas of the precentral gyri were measured in 12 cases of the classical sporadic form of ALS, and in 10 control subjects. The areas of motor neurons in the hypoglossal nuclei and in the ventral horns of segment L4 of the spinal cord were also measured. The number of neurons per 20 microns section of ventral horn or hypoglossal nucleus provided a more reliable index of severity of lower motor neuron loss at the time of death than did a semiquantitative score derived from clinical observations. Cortical neurons and lower motor neurons were significantly smaller in the cases of ALS than in the controls. In the cortex this change included, but was not confined to, the largest neurons. These observations indicate that shrinkage precedes neuronal death. There was no correlation, positive or negative, between the numbers of surviving lower motor neurons and the mean sizes of pyramidal cells in layer 5 of the corresponding areas of the precentral gyri. The absence of such a correlation indicates that functionally related cortical and lower motor neurons probably degenerate independently, and not from a transsynaptic effect. Neuronal shrinkage has been observed in other diseases in which interconnected systems of neurons degenerate. The possible association of shrinkage with cytoskeletal degradation is discussed.