Background. Transesophageal natural-orifice transluminal endoscopic surgery (NOTES) mediastinoscopy has been described as a feasible, less-invasive alternative to video-assisted mediastinoscopy (VAM). We aimed to investigate hemodynamic and respiratory effects during transesophageal NOTES mediastinoscopy compared with VAM. Patients and methods. This was a short-survival experiment in 20 female pigs randomized to NOTES (n = 10) or VAM (n = 10) mediastinoscopy. In the NOTES group, an endoscopist accessed the mediastinum through a 5-cm submucosal tunnel in the esophageal wall, and CO₂ was used to create the pneumomediastinum. Conventional VAM was carried out by thoracic surgeons. A 30-minute systematic exploration of the mediastinum was then performed, including invasive monitoring for hemodynamic and respiratory data. Blood samples were drawn for gas analyses. Results. All experiments except 2 in the NOTES group (one because of technical difficulties, the other because of thoracic lymphatic duct lesion) were completed as planned, and animals survived 24 hours. Also, 3 animals in the NOTES group presented a tension pneumothorax that was immediately recognized and percutaneously drained. VAM and NOTES animals showed similar pulmonary and systemic hemodynamic behavior during mediastinoscopy. Pulmonary gas exchange pattern was mildly impaired during the NOTES procedure, showing lower partial arterial oxygen pressure associated with higher airway pressures (more important in animals that presented with pneumothorax). Conclusions. NOTES mediastinoscopy induces minimal deleterious respiratory effects and hemodynamic changes similar to conventional cervical VAM and could be feasible when performed under strict hemodynamic and respiratory surveillance. Notably, serious complications caused by the injury of pleura are more frequent in NOTES, which mandates an improvement in technique and suitable equipment.