The cytopathology and loss of neurons was studied in 7670 neurons from the ventral horn of the third lumbar segment of the spinal cord of six sporadic motor neuron disease (MND) patients compared with 7568 neurons in seven age matched control subjects. A modified Tomlinson et al. [Tomlinson BE, Irving D, Rebeiz JJ. Total numbers of limb motor neurones in the human lumbosacral cord and an analysis of the accuracy of various sampling procedures. J Neurol Sci 1973;20:313-27] sampling procedure was used for neuronal counts. The ventral horn was divided in quadrants. Neuronal populations were also classified by the maximum cell diameter through the nucleolus. There was widespread loss of neurons in all quadrants of the ventral horn in MND. Size distribution histograms showed similar neuron loss across all populations of neurons. The dorsomedial quadrant contains almost exclusively interneurons and the ventrolateral quadrant mostly motor neurons. The cytopathology of neurons in the dorsomedial quadrant and of large motorneurons in the ventrolateral quadrant MND was similar. In the dorsomedial quadrant, neuron loss (56.7%) was similar to the loss of large motor neurons in the ventrolateral quadrant (64.4%). The loss of presumed motor neurons and interneurons increased with increased disease duration. There was no evidence that loss of presumed interneurons occurred prior, or subsequent, to loss of motor neurons. We conclude that, in sporadic MND, all neuronal populations in the ventral horn are affected and that interneurons are involved to a similar extent and in parallel with motor neurons, as reported in the G86R transgenic mouse model of familial MND. The increasing evidence of loss of neurons other than motor neurons in MND suggests the need for revising the concept of selective motor neuron vulnerability.