Endoscopic submucosal dissection (ESD) has enabled the collective resection and increased the accuracy of pathological diagnosis. However, ESD requires a long operation time, which results in increased doses of analgesics/sedatives, and causes worsening of respiratory and hemodynamic statuses. To reduce postoperative complications, we have applied ESD with CO(2) insufflation and general anesthesia. This study included 50 patients who underwent ESD for early gastric cancer, 25 with air insufflation and intravenous anesthesia (Air/IV group), and the remaining 25 with CO(2) insufflation and general anesthesia (CO(2)/GA group). Postoperative enlarged feeling of the abdomen was observed only in 1 of 25 patients in the CO(2)/GA group (P = 0.0416). Postoperative severe unrest was observed in none of the patients in the CO(2)/GA group and in 4 of 25 (16%) patients in the Air/IV group (P = 0.0371). CO(2) insufflation and general anesthesia are useful in stabilizing intraoperative conditions and reducing postoperative complications.