Background and Aims The role of endoscopic submucosal dissection (ESD) in Barrett’s early neoplasia is not well defined, with most studies originating from Asia and Europe. We aimed to assess the efficacy, safety, and results of ESD in Barrett’s esophagus (BE) with high-grade dysplasia (HGD) and early adenocarcinoma (EAC) across centers in the United States. Methods Multicenter retrospective analysis on 46 patients with BE who underwent ESD for BE-HGD or EAC, or both, between January 2010 and April 2015. The primary endpoint was the rate of en bloc resection. Secondary aims included rate of R0 (complete) and curative resection, a comparison of pre- and post-ESD histology, procedure-related adverse events, and rate of remission at follow-up. Results Median age was 69 years (range, 42-82 years). The median resected specimen size was 45 mm (range, 13-125 mm). En bloc and curative resection rates were 96% (44/46) and 70% (32/46), respectively. Most lesions (11/20; 55%) diagnosed as BE-HGD on biopsy were upstaged to intramucosal or invasive EAC on post-ESD histopathology. There were 4 early (<48 hours) adverse events (3 bleeding and 1 perforation), and all were treated endoscopically. Seven patients (15%) developed esophageal strictures that were managed endoscopically. Complete remission of BE neoplasia was found in 100% (32/32) of patients with curative resection at median follow-up of 11 months (range, 2-25 months). Conclusions This is the largest multicenter series of ESD for early neoplastic BE from the United States. ESD appears to be safe and effective, with high en bloc and curative resection rates in the treatment of early BE neoplasia.