Background: Laser therapy of esophageal carcinoma has been limited to management of malignant dysphagia. To investigate its cytoreductive potential, Nd:YAG laser tumor debulking was added to multimodality therapy. Methods: From 1994-1998, 29 patients with advanced locoregional esophageal carcinoma were enrolled in a prospective experimental study of high-dose neoadjuvant chemoradiotherapy together with endoscopic Nd:YAG laser photoablation. Comparisons were made to a retrospective cohort of 31 patients treated from 1990 to 1994 who underwent similar neoadjuvant chemoradiotherapy without laser debulking. Results: Laser dosage ranged from 3457 to 67,443 J (mean 21,832 [SD 16,999]) delivered in 1 to 6 (mean 2.6 [1.4]) treatment sessions. Actuarial analysis showed improved survival in the laser-treated group versus the reference group (30.1 months vs. 16.5 months; p = 0.047). Multivariable analysis of the impact of age, T-stage, N-stage, completion of neoadjuvant therapy, and laser debulking that included all patients in both treatment groups showed completion of therapy to be the most significant variable associated with survival. There were 3 complications related to laser therapy. Relief of dysphagia was achieved in 19 of 29 patients (66%) in the laser group versus 13 of 31 (42%) in the reference group. Conclusions: Malignant dysphagia may be more effectively treated by the addition of Nd:YAG laser therapy to aggressive multimodality therapy. Improved survival with the addition of laser debulking warrants longer follow-up and a prospective comparative trial. (Gastrointest Endosc 2002;55:674-9.)