© Mary Ann Liebert, Inc. 2016. Background: Investigations indicate that natural orifice translumenal endoscopic surgery (NOTES) procedures induce a less pronounced postoperative inflammatory response than open or laparoscopic surgery, inflicting less trauma. In NOTES procedures, no skin incision is performed. We compare the inflammatory response added by the type of incision by measuring C-reactive protein (CRP) and tumors necrosis factor-alfa (TNF-α). Methods: Twenty-seven pigs were randomized to open surgical, laparoscopic, or transgastric NOTES abdominal access. After completion of the accesses, no surgery was performed. All accesses were left open for 40 minutes followed by closure, animals were survived for 7 days. Blood samples were drawn at the start of the accesses, at 20 and 40 minutes during the procedure, and at postoperative day (POD) 1, 3, and 7. Analyses of CRP and TNF-α were performed. Results: CRP increased in all animals until POD1. This increase was greater in the open group (P = .006). No significant differences in CRP-levels were found at POD 1, 3, or 7. TNF-α showed a peak during the procedure, at 20 and 40 minutes, with normalization at POD1 for 1/3 of the open and laparoscopic animals, but not for the NOTES animals. Due to variations within the groups, no statistical difference was shown between them. At postmortem, 1/3 of the pigs in the laparoscopic and open groups had wound infections, while no NOTES animals showed infections. Conclusions: This study provides no statistically significant differences in inflammatory response after the different abdominal accesses. However, the lack of a TNF-α-peak in the NOTES group might indicate a less pronounced response, supporting the initial theories.