Background: Evidence for the routine use of robotic technology and its impact on short-term outcomes in colon cancer surgery is lacking. The aim of this study was to compare the surgically induced systemic stress response and clinical and patient-reported outcomes for patients undergoing robot-assisted or laparoscopic colon cancer surgery. Methods: In this double-blinded superiority RCT completed between August 2021 and March 2023, patients with stage 1–3 colon cancer were randomized in a 1 : 1 ratio to undergo either robot-assisted or laparoscopic colon cancer surgery. The primary outcome was changes in the systemic stress response, characterized by C-reactive protein expression in the first three postoperative days. Secondary outcomes were intraoperative and postoperative complications and patient-reported outcomes. The latter included quality of recovery-15 and pain intensity using a visual analogue scale. Results: In total, 128 patients were screened for potential inclusion in this study; 50 patients (25 in the robot-assisted group and 25 in the laparoscopic group) were included in the final follow-up and analysis. The postoperative C-reactive protein response was higher on the first postoperative day in the laparoscopic group (mean difference = 19.88 mg/l, 95% c.i. 3.89–35.86; P = 0.045). No statistically significant differences were noted for C-reactive protein expression on the second and third postoperative days. Conclusion: Adopting robot-assisted surgery for stage 1–3 colon cancer is associated with a reduction in the surgical stress response. Registration number: NCT04687384 (http://www.clinicaltrials.gov). The aim of this RCT was to investigate the perioperatively induced systemic stress response and clinical and patient-reported outcomes for patients undergoing robot-assisted or laparoscopic colon cancer surgery. Adopting RCS resulted in a lower stress response. However, it did not cause an improvement in recovery rates or patient-reported outcomes. [ABSTRACT FROM AUTHOR]