It has been suggested that the primary site of damage in motor neuron disease (MND) is the cortical motor neuron, with secondary degeneration of spinal motor neurons. To test this hypothesis, we sought to determine if loss of corticomotoneurons in MND precedes spinal motor neuron loss. The density of corticomotoneurons was measured in 18 MND and 9 control cases using 10-microns horizontal sections of motor cortex in the hand/arm region. The density of spinal motor neurons was measured in 10-microns transverse sections of the lower cervical spinal cord. Corticomotoneuron and spinal motor neuron densities were decreased in MND cases compared to controls, but in MND cases there was poor correlation (r2 = 0.06) between corticomotoneuron and spinal motor neuron densities. The results indicate that corticomotoneuron and spinal motor neurons are lost at different rates in different MND patients, and that corticomoteneuron loss is unlikely to be a primary event in MND.