Background & Aims: Barrett adenocarcinoma (BA+) and gastric adenocarcinoma comprise a related group of neoplasms that nevertheless have some distinct clinicopathologic characteristics. This study aimed at defining critical molecular abnormalities that may underlie differences between BA+ and gastric adenocarcinomas. Methods: We used comparative genomic hybridization for the analyses of 34 xenografts of adenocarcinomas that arose from esophageal or gastric origin. Results: All tumors, except one, exhibited DNA copy number alterations. Losses in 4q and 14q and gains at 2p and 17q were more frequent in proximal (esophageal, gastroesophageal junction [GEJ], and cardia) tumors than in distal (body and antrum) tumors (P ≤ 0.050). These changes were significantly higher in BA+ compared with distal tumors (P ≤ 0.040). In addition, losses in 5q and gains at 20q were significantly higher in BA+ than in distal cancers (P ≤ 0.040). Losses in 5q and 8p and gains at 2q, 6p, 12p, and 20q were significantly more frequent in BA+ tumors (P ≤ 0.050) than in GEJ and cardiac tumors without associated Barrett's esophagus. Additionally, losses in 14q, which were common in proximal tumors, were more often seen in BA+ (P = 0.100) than in other proximal tumors. Conclusions: Although these adenocarcinomas share some common genetic alterations, the differences in the DNA copy numbers in BA+ cases suggest that unique genetic alterations may be involved in these cancers' development.