Background: In the CROSS trial, neoadjuvant chemoradiotherapy (CRT) prior to surgery for esophageal (E) and gastroesophageal junction (GEJ) cancers was found to improve survival. However, 10-year data did not show benefit in reducing isolated distant metastases. Addition of full-dose induction chemotherapy (CT) prior to CRT could provide early systemic disease control in addition to enhanced local control. We evaluated induction CT with FOLFOX followed by CRT and surgery in patients with E/GEJ cancers. Methods: This single-arm, phase II clinical trial investigated trimodality therapy in clinically staged II/III resectable cancers of the E/GEJ (NCT03110926). Treatment schedule was: 6 weeks of mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) followed by 5.5 weeks of CRT with weekly paclitaxel and carboplatin and 41.4-45 Gy of radiation (RT) and surgery. Primary endpoint was 2-year relapse-free survival (RFS) measured from time of surgery to date of first recurrence or death and was calculated by the Kaplan-Meier method. Overall survival (OS) and key pathologic findings were secondary outcomes. Results: In total, 41 patients enrolled with mean age of 63.1 years; 78% were male. Almost all (95%) were adenocarcinoma. Median duration of follow-up was 2.08 years. Most primary tumors were located in the GE junction (68.3%). Treatment was well tolerated: 95% patients completed all FOLFOX cycles, 98% received the pre-specified RT dose, and 36 of 41 (87.7%) went on to have surgery (1 elected observation after complete clinical response). R0 resection occurred in 97% of those that went on to have surgery. At least partial pathologic response was found in 30 of 36 (83.3%); 8 of 36 (22%, CI 10.1-39.2%) had a pathologic complete response (pCR) and 20 of 36 (55%) had pCR or near-complete response (NCR). At the time of analysis, 2-year RFS was 71.5% (CI 52.1-84.2) and the median RFS was 3.1 years; median OS was not reached. At time of follow-up, 85% (17 of 20) of those with NCR and PCR were relapse-free. Conclusions: Our study demonstrates a high treatment completion rate when FOLFOX was administered prior to CRT and surgery for E/GEJ cancers. Almost all patients had R0 resection and over half had NCR or pCR response. Short-term follow-up RFS and OS demonstrate promising efficacy for this approach in a sample almost exclusively of adenocarcinoma tumors. Strategies to implement induction FOLFOX or FLOT either with or without CRT should continue to be explored in larger studies. Clinical trial information: NCT03110926.