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Background and Aim: Avoiding abdominal incisions is one of the unique features of natural orifice specimen extraction (NOSE) surgery. There has been no consensus on whether the avoidance of abdominal incisions can reduce the systemic inflammatory response after NOSE surgery. This study was designed to evaluate the safety and feasibility of transanal NOSE, especially the inflammatory response after transanal NOSE versus mini‐laparotomy (LAP). Methods: A total of 172 colorectal cancer patients who underwent transanal NOSE were matched with 172 patients who underwent LAP for colorectal cancer. Clinical characteristics, pathological features, perioperative parameters, and indicators of the inflammatory response were collected and compared. The inflammatory response was assessed by measuring body temperature, neutrophil count, C‐reactive protein levels, and procalcitonin levels. Results: Patients in the NOSE group had better short‐term outcomes, such as lower incidence of wound infection, less postoperative pain, less need for anesthetic drugs, and faster recovery of intestinal function. Regarding the inflammatory response, the average body temperature of patients in the NOSE group was higher on postoperative day (POD) 2 than that in the LAP group. A higher median neutrophil count and C‐reactive protein levels were observed in the NOSE group on POD3 and POD5 than was observed in the LAP group. Conclusions: Transanal NOSE is safe and feasible for colorectal cancer, with better short‐term outcomes. Although transanal NOSE produced a larger systemic inflammatory response than LAP in the early postoperative stages, this response did not appear to translate into infectious morbidity. [ABSTRACT FROM AUTHOR]