OBJECTIVES: The aim of this study was to determine whether specialized intestinal metaplasia recurs after complete laser ablation and to evaluate the persistence of colon epithelial protein in esophageal mucosa after laser ablation as a predictor of recurrence. METHODS: A total of 31 patients with specialized intestinal metaplasia (Barrett's esophagus) underwent laser photoablation. Investigators without knowledge of treatment status evaluated serial hematoxylin and eosin-stained slides, Alcian blue-stained slides, and immunohistochemistry for the detection of colon epithelial protein (mAb Das-1). RESULTS: Endoscopic ablation of specialized intestinal epithelium was accomplished in 21 patients after 6.5 ± 1.2 laser sessions. Complications included one perforation, one UGI bleed and one stricture. Of eight post-laser recurrences, seven were successfully re-ablated; one developed adenocarcinoma requiring esophageal resection. Cardia-type mucosa was present by biopsy at the time of complete ablation in all eight recurrent cases despite a normal endoscopic appearance. Colon epithelial protein was detected in all 31 patients before ablation, six of 21 completely ablated patients before they recurred and all eight recurrences. Only two of 15 patients, colon epithelial protein negative at the time of complete ablation, developed recurrent Barrett's esophagus. Thus, cardia-type mucosa and persistent colon epithelial protein staining after complete ablation of specialized intestinal epithelium were predictors of future recurrence (p < 0.001). CONCLUSIONS: Specialized intestinal epithelium was ablated by neodymium:yttrium-aluminum-garnet laser but recurred in eight of 21 (38%) of patients. Colon epithelial protein was present in all primary (31 of 31) and all recurrent (eight of eight) Barrett's esophagus. Recurrent specialized intestinal metaplasia may be deep to squamous epithelium. Replacement of specialized intestinal mucosa by cardia-type mucosa and persistence of colonic epithelial protein are predictors of recurrent specialized intestinal mucosa before its endoscopic or histological detection. Laser ablation of Barrett's epithelium is an investigational intervention that should be restricted to research protocols.