Complete response to neoadjuvant therapy, determined by pathologic examination of the resection specimen (pCR), is associated with a favorable outcome in esophageal adenocarcinomas (EAC), but there is significant heterogeneity in survival reported within this group. Our aim was to determine predictors of disease recurrence (DR) and survival in EAC patients with pCR to neoadjuvant therapy. A total of 93 EAC patients with pCR to neoadjuvant therapy were identified, and a predetermined set of clinicopathologic variables was examined, including patient age, sex, tumor location, pretreatment tumor size, endoscopic ultrasound T and N stage, histologic tumor type, and grade in pretreatment biopsies. The esophagectomy specimens were evaluated for the extent of sampling of the tumor bed, depth of treatment-related changes, presence of treatment effect in lymph nodes, and the total number of lymph nodes examined. Complete histologic examination of the tumor bed was the most significant predictor of favorable outcome for both DR (hazard ratio [HR]=0.42; 95% confidence interval [CI]: 0.21-0.82; P=0.011) and disease-specific mortality (HR=0.40; 95% CI: 0.22-0.70; P<0.01). The presence of a high-grade adenocarcinoma component in pretreatment biopsies (HR=2.19; 95% CI: 1.22-3.94; P<0.01) was associated with a higher disease-specific mortality, and involvement of the gastroesophageal junction (HR=2.37; 95% CI: 1.11-5.06; P=0.026) was associated with a higher rate of DR. Heterogeneity in outcomes for EAC patients with pCR to therapy can be explained by adequacy of histologic examination of the tumor bed, high tumor grade, and involvement of the gastroesophageal junction.