INTRODUCTION: Single-port or single-incision cholecystectomy with current rigid laparoscopic devices is limited by in-line visualization, restricting the ability to approach the surgical site with proper angles and instrumentation. A single-port access system with articulating arms and strong instrumentation should minimize these issues. The TransEnterix system may facilitate safe and straightforward single-port surgery. METHODS: The TransEnterix single-port surgery system was used in both survival and nonsurvival porcine laparoscopic cholecystectomies under animal use committee approval. Nonsurvival procedures compared four standard laparoscopic with four single-port cholecystectomies from a histologic perspective. Five single-port swine laparoscopic cholecystectomy procedures were completed in sterile conditions, and all animals survived for 1 week postoperatively. Standard surgical clips were used for both cystic duct and artery ligation. At sacrifice, both gross and microscopic histology were obtained for assessment of surgical complications. RESULTS: All cholecystectomies were successfully completed with the TransEnterix single-port system. Operative time for the survival procedures averaged 39.4 (range 18-66) min. Histology of the acute specimens showed less inflammation at the single-port site compared with the trocar sites from the standard cholecystectomy. At sacrifice, no complications were identified. CONCLUSIONS: The TransEnterix system is safe and straightforward for completing single-port cholecystectomy in this limited porcine series. Port site inflammation is reduced compared with standard laparoscopic trocars.