Background: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) may reduce perioperative complications and improve functional recovery. Methods: In this randomized controlled trial, 112 patients with resectable intrathoracic esophageal cancer were randomly assigned to RAMIE or OTE. The composite primary endpoint was the occurrence of overall postoperative complications (modified Clavien–Dindo classification (MCDC) grade 2-5). Results: Postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) (RR 0.74 (0.57-0.96; P = 0.02). RAMIE resulted in a less median blood loss (400ml versus 568ml, P < 0.001), a lower percentage of surgery-related complications (RR 0.74 (0.57-0.96; P = 0.02), pulmonary complications (RR 0.54 (0.34-0.85; P = 0.005) and cardiac complications (RR 0.47 (0.27-0.83; P = 0.006)) and lower mean postoperative pain (visual analogue scale, 1.86 versus 2.62; p < 0.000) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group (RR 1.48 (1.03–2.13; P = 0.038)) with better quality of life score at discharge (mean difference quality of life score 13.4 (2.0-24.7, p = 0.02) and 6 weeks post-discharge (mean difference 11.1 quality of life score (1.0-21.1; p = 0.03)). Mean costs for RAMIE were €34.892 and mean costs for OTE were €39.463 (p = 0.07). Oncological outcomes at short term (radicality, number of lymph nodes) and long term (overall and disease-free survival) were equal at a medium follow up of 38 months. Conclusions: RAMIE resulted in a lower percentage of overall, surgery-related and (cardio)pulmonary complications with lower postoperative pain, better quality of life and a better short term postoperative functional recovery compared to OTE. Oncological outcomes were equal. This randomized controlled trial provides evidence for the use of RAMIE to improve postoperative outcome in patients with resectable esophageal cancer. Clinical trial information: NCT01544790