Background: Neoadjuvant chemoradiation followed by esophagectomy is the standard of care in advanced EC. While 5FU based chemoradiation has been a common regimen in the past, its utilization has declined in recent years as the CROSS trial study regimen of carboplatin/paclitaxel has become widely adopted. A prospective evaluation of the CROSS regimen compared to the 5FU based regimen was never performed. The aim of this study is to report our institutional experience with these two chemotherapy regimens. To the best of our knowledge, this is the largest retrospective study comparing the two types of chemotherapy regimens. Methods: We performed an IRB-approved retrospective review of a prospectively maintained institutional cancer registry. EC patients who completed trimodality therapy with either carboplatin/paclitaxel or 5FU/platinum were identified and divided into groups based on their chemotherapy regimens. Multivariable logistic regression was used to analyze pathologic complete response (pCR) rates, while the Kaplan–Meier and Cox proportional hazards models were utilized to evaluate DFS and OS. Analytical models were adjusted for age, stage, radiation dose, histology sub-type, and time interval from completion of neoadjuvant therapy to surgery. Results: 224 patients treated between January of 2007 and July of 2017 were identified . Of this group, 139(62%) had received Carbo/Taxol, while 85 (37%) had received 5FU/platinum. There was no increase in the odds of pCR with 5FU based chemo compared to CROSS regimen (OR = 2.68, P = 0.671). Furthermore, the OS and DFS of 159 patients(80 5FU/platinum, 77 carbo/taxol) with median follow up of ~ 5 yrs were not statistically different with HR 1.08 (0.6-1.7) and P value 0.71. Conclusions: Neoadjuvant chemoradiation with 5FU/platinum in resectable EC is not associated with higher rates of pCR, DFS and OS compared to the CROSS regimen of carbo/taxol. Those findings will need to be validated in a larger cohort.