INTRODUCTION: The advantages of transanal total mesorectal excision (taTME) would be a reduction of the hernia rate and surgical trauma. The present study reports data for patients undergoing taTME and compares the post-operative immune response in taTME with those of conventional laparoscopic surgery (CLS) and single-port laparoscopic surgery (SPLS). METHODS: A comparative cohort study in patients with rectal cancer undergoing taTME. C-reactive protein (CRP) and white blood cell count (WBC) were measured pre-operatively and on post-operative days one, two, three and four. RESULTS: A total of 40 patients were included in taTME, 20 patients in CLS and 20 in SPLS. Patients’ demographics (except for clinical staging), R0 resection and post-operative complication rates were comparable. The length of abdominal incisio-n was significantly lower by taTME than by both SPLS and CLS (p < 0.001). Distant resection margin was shorter in the taTME group (p < 0.01), and the quality of specimen differed between groups (p < 0.01). CRP and WBC increased significantly in each group (p < 0.05), but there was no difference between the groups. CONCLUSIONS: There is no difference in the inflammatory response in patients with rectal cancer undergoing taTME surgery compared with CLS and SPLS. We therefore conclude that the length/presence of abdominal incision does not further reduce the post-operative inflammatory stress response in minimally invasive procedures. The surgical trauma extends beyond the abdominal incision and depends on the intra-abdominal handling of the tissue.