Background: While trimodal therapy with neoadjuvant carboplatin/paclitaxel (CP) has demonstrated superiority over surgery alone for treatment of locally advanced esophageal cancer (LAEC), its superiority to alternative regimens is yet unproven. Here we directly compare CP against cisplatin/5-FU (CF), the historical standard, as a component of trimodal therapy for LAEC. Methods: Patients receiving trimodal therapy with either CP or CF for LAEC at a single institution from 2002 to 2017 were included in this retrospective study. Clinical data, treatment regimen, and tumor response were obtained from medical records. The primary outcome was pathologic complete response (pCR). Secondary outcomes were overall (OS) and disease?free survival (DFS), calculated from the date of surgery until death (OS & DFS) or first recurrence (DFS only). Primary outcomes were measured with logistic regression; survival was estimated with Kaplan?Meier and Cox Proportional Hazards models. Patient characteristics were compared with Student?s T and chi square tests. Results: 326 patients were included in this study. 187 patients (57%) received CP; 139 patients (43%) received CF. Mean follow-up was 36 months. The CP group was older (mean age 64 vs. 62, P < .01) and had a higher rate of hypertension (49% vs. 35%, P = .02) than the CF group. Distribution of tumor stages was similar between groups (P = .3). CF was associated with improved pCR compared to CP in both univariate (OR 1.8, P = .02) and multivariate (OR 2.2, P = .01) analysis. CF showed improved median OS compared to CP (42 vs. 29 months, P = .04), and trended toward improved DFS (27 vs. 17 months, P = .08). In multivariate analysis controlling for age, performance status, and comorbidities, CF was associated with improved OS (HR .68, P = .03) and DFS (HR .67, P = .02) compared to CP. Conclusions: Trimodal therapy with CP has become the standard of care for curative treatment of LAEC, yet most studies compare it against surgery alone rather than trimodal therapy with an alternative regimen. Here we directly compare CP to the historical standard regimen (CF), finding that CP is associated with worse tumor response and survival. These findings warrant further investigation with prospective studies.