Total laparoscopic hysterectomy (TLH) may be indicated in patients with deep infiltrative endometriosis (DIE) to treat severe chronic pelvic pain symptoms, recurrences, or co-existing uterine disease. This study discusses the challenges and specific operative and postoperative considerations in patients submitted to TLH and excision of DIE, in comparison with those undergoing a procedure for other benign indications. Patients undergoing TLH and excision of DIE were included (N = 18, group 1). These were matched with cases, treated with TLH for other benign indications during the same period (2010–2019), at a 2:1 ratio (N = 36, group 2). The two groups were compared with regards to their characteristics, and intraoperative and postoperative data, including operative time, estimated blood loss (EBL), hospital stays, and rates of complications. In group 1, median DIE nodule size was 2.5 cm (range: 1.3–4.2). Simple hysterectomy was performed in 10, and a more extended procedure in 8 cases. All nodules were removed from the bowel wall using the shaving technique. Average EBL was significantly higher (p = .027), and duration of surgery and hospital stays longer (p = .003, and p = .0001, respectively), in group 1 vs. group 2. The rates of long-term (L-T) complications were higher in group 1 but not to a significant level (p = .087). Analysis within the DIE group showed that operative time was significantly related to nodule size, type of hysterectomy (p = .021), presence of adenomyosis (p = .041), uterine size ≥12weeks (p = .039), and the occurrence of L-T complications (p = .016). Increasing nodule size and an extended procedure (p = .005) increased significantly the EBL, which had also a significant effect on the risk of L-T complications (p = .006). TLH in DIE patients is a different, complex and potentially more dangerous procedure compared with TLH for other benign indications. Thorough knowledge of retroperitoneal anatomy, a clear operative plan, and excellent laparoscopic skills are necessary for concomitant radical excision of lesions, with low rates of adverse events.