Achalasia is characterized by failure of relaxation of the lower esophageal sphincter and absence of progressive peristalsis in the esophageal body. Few data are available regarding the morphologic features of achalasia, in particular its histologic progression. The esophagi of 42 patients with achalasia treated with total thoracic esophagectomy were examined histologically in order to systematically identify morphologic features of clinically unresponsive achalasia and to determine what could be learned about the disease's evolution. In all cases, myenteric ganglion cells within the esophageal body were markedly diminished, with 20 specimens having none. Twenty specimens had residual ganglion cells in the proximal esophagus, and 15 specimens had a few randomly distributed ganglion cells in the mid- and distal portions of the esophagus. Inflammation within myenteric nerves, present in all cases, generally consisted of a mixture of lymphocytes and eosinophils, occasionally with plasma and mast cells. Focal replacement of myenteric nerves by collagen occurred in all cases, and there was almost complete replacement in several cases. Actual destruction of the residual ganglion cells was not seen. The resected esophagi also shared extramyenteric morphologic features. Some features probably stemmed from physiologic obstruction, such as muscular hypertrophy, mainly of the muscularis propria (all cases), with secondary degeneration and fibrosis (29 cases), and eosinophilia of the muscularis propria (22 cases). Other changes, probably resulting from chronic stasis of ingested materials in the lumen, included diffuse squamous hyperplasia (all cases), lymphocytic mucosal esophagitis (28 cases), lymphocytic inflammation of the lamina propria and submucosa with prominent germinal centers (all cases), and submucosal periductal or glandular inflammation with complete loss of submucosal glands in half of the cases. One patient had high-grade squamous dysplasia, and another had superficially invasive squamous cell carcinoma. A third group of changes was probably due to previous esophagomyotomy, including abnormal gastroesophageal reflux, as shown by pH reflux testing (13 cases) and Barrett's mucosa (four cases). In one case of Barrett's there was low-grade dysplasia. Clinically unresponsive, surgically resected achalasia has almost total loss of ganglion cells, and widespread destruction of myenteric nerves has already occurred. The only active component is myenteric inflammation. However, it cannot be determined whether this inflammation is a manifestation of ongoing nerve destruction or whether it is a secondary phenomenon.