The accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) lumen causes a cellular stress response termed the unfolded protein response. Although ER stress has been implicated in various neurodegenerative diseases, the morphological features of aggregated proteins in ER lumina that may cause neurodegeneration have not been well characterized. We examined anterior horn neurons using immunohistochemistry and electron microscopy in 12 sporadic amyotrophic lateral sclerosis (ALS) patients and 12 controls. Approximately 2.6% of both normal-appearing and degenerated motor neurons in ALS cases were immunostained for the ER chaperone protein glucose-regulated protein 78, and approximately 0.1% of these neurons was glucose-regulated protein 78 positive in controls (p = 0.0004). Amyotrophic lateral sclerosis cases also tended to have glucose-regulated protein 78-positive motor neurons more frequently than control cases (p = 0.08). By electron microscopy,neurons in ALS patients showed accumulations of amorphous and granular material suggestive of misfolded or unfolded proteins in dilated predominantly normal-appearing ER. There were also wavy membranous structures extending from the ER membranes that lacked membrane-bound ribosomes, electron-dense material resembling Bunina bodies, Hirano bodies, honeycomb-like structures, and membrane-particle complexes associated with the ER in these neurons. Control sample neurons demonstrated none of these features. These ER alterations suggest that the unfolded protein response is activated in motor neurons in ALS patients and provide the first morphological evidence that ER stress may be involved in the neurodegeneration of motor neurons in early stages of sporadic ALS.