Introduction Esophageal adenocarcinoma is a lethal malignancy which is increasing in incidence, and many patients receive chemotherapy as part of their treatment. We have previously demonstrated that esophageal adenocarcinoma-derived cell lines respond to treatment with estrogen receptor modulators, such as tamoxifen. Reports from breast cancer suggest that tamoxifen may attenuate the efficacy of other chemotherapeutic agents. We have therefore assessed the response of esophageal adenocarcinoma cell lines to tamoxifen therapy when given in combination with conventional agents. Methods Two estrogen receptor (ER)-positive esophageal adenocarcinoma cell lines (OE-19 and OE-33) were treated with combinations of tamoxifen, cisplatin and 5-fluorouracil (5-FU). Effects on cell viability were measured using an MTS assay, and cell death was detected with annexin V/propidium iodide flow cytometry. To assess whether the efficacy of tamoxifen in these cell lines might be relevant to the clinical setting, we analyzed ER status in 10 esophageal adenocarcinoma tissue specimens by immunohistochemistry. Results IC50 values (μM) for OE-19 and OE-33 were 11.2 and 7.1 for tamoxifen, 19.6 and 4.7 for cisplatin, and 1.7 and 5.9 for 5-FU, respectively. Cell death was detected in 11.9% and 15.8% of cells treated with tamoxifen, 7.9% and 8.7% cells treated with cisplatin, and 3.6% and 8.6% cells treated with 5-FU at their IC50s. The addition of tamoxifen to cisplatin increased cell death by 11.4% in OE-19 (p < 0.0001) and 16.3% in OE-33 (p < 0.0001). Similarly, the addition of tamoxifen to 5-FU increased cell death by 11.6% in OE-19 (p < 0.0001) and 15.9% in OE-33 (p < 0.0001). Eight of 10 tissue specimens showed positive staining for ERα and 7 of 10 for ERβ. Conclusions In a cell culture model the addition of tamoxifen to conventional chemotherapy appears to be both feasible and beneficial. Expression of ERα and ERβ was also confirmed in esophageal adenocarcinoma tissues.