OBJECTIVE To localize and analyze the anatomic distribution of upper motor neuron (UMN) and lower motor neuron (LMN) loss in patients with ALS early in their disease when motor manifestations were still relatively focal using clinical examination signs. METHODS We reviewed records of 100 patients with ALS who were evaluated when the diagnosis was first established or suspected. From the patient history, we ascertained the body region of first symptoms and the time course. From the physical examination, we separately graded severity of UMN and LMN signs in each body region, indexed these to the body region of first symptoms, and sorted and analyzed the data. RESULTS Motor manifestations began in one body region in 98% of patients. UMN and LMN signs were both maximal in these same body regions, but they were independent of each other in severity and their outward distribution, which conformed to neuronal anatomy. The outward distribution of both UMN and LMN signs seemed more directed to caudal body regions than to rostral ones. CONCLUSIONS Motor neuron degeneration in ALS is a focal process at both upper and lower motor neuron levels of the motor system. At each level, it begins corresponding to the same peripheral body region and then advances contiguously and separately to summate over time.