The pathogenesis of dysphagia in achalasia and diffuse esophageal spasm (DES) is not understood completely, and the primary site of damage in these two entities is not known. This project was undertaken to study the ultrastructural changes present in the muscular wall of the esophagus in eight patients with achalasia and nine patients with DES, compared with seven controls. The ultrastructural alterations in the smooth muscle of all patients were neither pronounced nor consistent. However, nonspecific changes, including filament disarray, mottling of the fiber density in myocytes, thick and long cytoplasmic dense bodies, long dense plaques, and few nexus junctions were seen in both achalasia and DES. In addition, the smooth muscle cells in achalasia exhibited nuclear and cytoplasmic inclusions. Statistical analysis of the number of muscle cells per unit area suggested that the gross thickening of the muscular wall of the esophagus in cases of DES is because of hyperplasia and not hypertrophy of muscle cells. A striking change seen in achalasia esophagi and a few cases of DES, as compared to the controls, was the marked loss of small nerve fibers and the paucity of granules in the remaining fibers. This study points to a neurogenic pathogenesis for dysphagia in achalasia with secondary nonspecific changes in the smooth muscle in these two diseases. No nerve abnormalities were noticed in DES.