Background: Tumor immune cell infiltration has been shown to influence the prognosis and treatment prediction in several types of cancer and the focus has largely been on the innate immune system as well as the cell-mediated immune response. There are, however, recent findings suggesting an important role for the humoral immune system in stemming cancer progression. The aim of this study was therefore to investigate the prognostic impact of B cell and plasma cell infiltration in esophageal and gastric cancer. Methods: Immunohistochemical expression of the pan B-cell marker CD20 and plasma cell markers CD138 and immunoglobulin kappa C (IGKC), were analyzed in tissue microarrays (TMA) from primary tumors in a cohort of 174 consecutive, surgically treated cases of gastro-esophageal adenocarcinoma. A multiplier of intensity and fraction was calculated, and the median value was used for prognostic cut-off. Kaplan-Meier analysis, univariable and multivariable Cox regression analysis, adjusted for age, TNM-stage, resection margins and adjuvant chemotherapy, were used to determine the impact of IGKC, CD20 and CD138 expression on overall survival (OS). Results: A high density of IGKC+ plasma cells was significantly associated with a prolonged survival in esophageal (HR 0.41, 95% CI 0.21-0.78) and gastric adenocarcinoma (HR 0.50, 95% CI 0.28-0.88). A high density of CD138+ plasma cells was also significantly associated with prolonged survival but only in gastric adenocarcinoma (univariable HR 0.48, 95% CI 0.27-0.86, multivariable HR 0.51; 95% CI 0.27-0.97)). IGKC+ plasma cell expression remained significant in multivariable analysis, for esophageal (HR 0.50, 95% CI 0.26-0.97) and gastric adenocarcinoma (HR 0.50, 95% CI 0.27-0.94). There was no significant association between the density of CD20+ cells and survival. Conclusions: Our findings show, for the first time, that a higher density of stromal plasma cells correlates with a prolonged survival in both esophageal and gastric adenocarcinoma. These are new and encouraging findings that warrant further evaluation in additional patient cohorts.