Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. The aim of this study is to assess the correlation between microvascular density and disease progression of non-dysplastic Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and invasive carcinoma in the superficial aspects of the tissue. Archival histological specimens from two referral centers for Barrett's esophagus and esophageal cancer were selected for review. A total of 160 regions marked according to histological grade were assessed with digitally interactive software to measure microvascular density. This was quantified in three levels: 0-50, 50-100 and 100-150 μm. In the areas of gastric cardia, Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and cancer, microvascular density was significantly different (P<0.0001) among the five groups in the most superficial 150 μm of the mucosa. Furthermore, when examining the pairwise difference between the groups, there was a significant difference between cancer and each of the lower grades of histology (P<0.05) and between high-grade dysplasia and each of the lower grades of histology (P<0.05). These statistically significant differences were preserved in examining the depth at the most superficial 50 μm. We have used digital pathology to demonstrate a significant and stepwise increase in microvascular density, which supports the hypothesis that angiogenesis has a key role in Barrett's carcinogenesis. Furthermore, the differences in the most superficial mucosal layers are consistent with findings of increased vascularity by depth-restricted imaging modalities.