The ESOPEC trial showed that perioperative chemotherapy with fluorouracil (FU)/leucovorin/oxaliplatin/docetaxel (FLOT) improved survival in patients with nonmetastatic esophageal adenocarcinoma compared with preoperative chemoradiotherapy with CROSS (41.4Gy/carboplatin/paclitaxel). For this analysis, patients from the ESOPEC trial who underwent tumor resection were eligible. The reported end points here include cause-specific mortality, recurrence-free survival (RFS), and sites of recurrence. Of the 438 patients enrolled in ESOPEC, 192 of 221 (86.9%) FLOT patients and 179 of 217 (82.5%) CROSS patients underwent tumor resection. After a median follow-up of 56 months, 178 experienced disease recurrence (81 FLOT; 97 CROSS) and 28 died without recurrence (12 FLOT; 16 CROSS). The 3-year RFS rate was 54.5% in FLOT patients versus 39.0% in CROSS patients (hazard ratio [HR], 0.67 [95% CI, 0.51 to 0.89]; P = .005). Locoregional recurrence occurred in 39 FLOT versus 32 CROSS patients (3-year cumulative incidences 20.2% v 17.4%, HR, 1.00 [95% CI, 0.62 to 1.61]; P = .99). Distant recurrence occurred in 64 FLOT versus 89 CROSS patients (3-year cumulative incidences 31.5% v 47.2%, HR, 0.59 [95% CI, 0.43 to 0.82]; P = .002). Compared with CROSS, perioperative chemotherapy with FLOT improved survival through better systemic tumor control with a reduction in distant tumor recurrences, while locoregional efficacy was similar.