Occasionally, patients with Barrett's-associated adenocarcinoma who received preoperative chemoradiotherapy (chemrad) show prominent mucin pools in their resection specimen, but the prognostic significance of this finding has never been investigated. The purpose of this study was to evaluate the clinical and pathologic features, and prognostic significance, of prominent mucin pools in 21 patients identified from a cohort of 192 consecutive cancer patients (prevalence rate, 10.9%) who had an esophagectomy (post-chemrad) for adenocarcinoma. The clinical and pathologic features and follow-up data were evaluated in 21 patients with adenocarcinoma of the esophagus and with prominent mucin pools (male-to-female ratio, 21:0; mean age, 61 years) and compared with a control group of 19 consecutive chemrad-treated and stage-matched esophageal adenocarcinoma patients who had either minimal microscopic (9 cases) or no (10 cases), residual disease present in their resection specimen (male-to-female ratio, 18:1; mean age, 62 years). Of the 21 study patients, 7 (33%) had acellular mucin pools with no residual tumor, 7 (33%) showed rare isolated tumor cells within mucin pools, and 7 (33%) had acellular mucin pools with microscopic foci of residual adenocarcinoma in tissue adjacent to, but not within, mucin pools. In total, 2 cases (9%) showed mucin pools limited to the submucosa, 5 (24%) showed involvement of the muscularis propria, and 14 (67%) showed mucin pools within the muscularis propria and adventitia. Four cases (19%) showed involvement of the radial resection margin with acellular mucin pools. Thirteen study patients (62%) contained acellular mucin pools within regional lymph nodes. A significantly higher proportion of patients with prominent mucin pools had mucinous adenocarcinoma prior to neoadjuvant therapy, compared with control patients without mucin pools (12 of 21 (57%) vs. 1 of 19 (5%), P < 0.001). Upon follow-up (mean, 27 months; range, 5-84 months), none of the study patients with prominent mucin pools died of disease (0%), in comparison to 5 of 19 (26%) control patients (mean follow-up, 27 months; range, 3-64 months) (P = 0.02). None of the patients who had acellular mucin pools involving the radial margin developed recurrence or metastasis or died of disease. Prominent mucin pools in resection specimens from patients with Barrett's esophagus-associated adenocarcinoma who received preoperative chemrad are associated with mucinous tumors and are not associated with poor survival, even when acellular mucin pools involve the radial margin, and, thus, should not be interpreted as evidence of residual viable adenocarcinoma.