Abstract Objective: To evaluate the safety and effects on health-related quality of life (HRQOL) of radical excision of deeply infiltrating endometriosis (DIE) in the cul-de-sac. Patients and Methods: This study included 390 patients with pathologically proven DIE in the cul-de-sacwho underwent laparoscopic surgery between January 2000 and December 2011. The preoperative and postoperative visual analog scale (VAS) pain scores and HRQOL data from the 36-item Short Form (SF-36) questionnaire were recorded in 343 patients. Surgical outcomes, complications, and HRQOL were compared between patients who underwent hysterectomy and those who did not. Data were analyzed using the paired t test, Student's t test, and Pearson's correlation analysis. Results: In the group overall, the VAS pain score and all SF-36 scales improved after surgery. In patients who underwent hysterectomy, all SF-36 scales improved except physical functioning, role-physical, general health, and vitality. In patients who did not undergo hysterectomy, all SF-36 scales improved except general health. There were significant associations between gonadotropin-releasing hormone agonist therapy and SF-36 mental health, SF-36 mental component summary, and oral medication use. The VAS pain score and SF-36 body pain score showed the greatest improvement, and the SF-36 general health score showed the least improvement. Patients who underwent hysterectomy had more severe disease and poorer surgical outcomes than those who did not undergo hysterectomy. Conclusions: Laparoscopic radical excision of DIE in the cul-de-sac is safe and significantly improves HRQOL, especially in terms of pain. The severity of endometriosis may affect the degree of improvement in HRQOL scores.