The aim of this study was to evaluate the feasibility of opioid-free anesthesia (OFA) in open radical cystectomy (ORC) with urinary diversion and to assess the impact on recovery of gastrointestinal function. We hypothesized that OFA would lead to earlier recovery of bowel function. A total of 44 patients who underwent standardized ORC were divided into two groups (OFA group vs. control group). In both groups, patients received epidural analgesia (OFA group: bupivacaine 0.25%, control group: bupivacaine 0.1%, fentanyl 2 mcg/mL, and epinephrine 2 mcg/mL). The primary endpoint was time to first defecation. Secondary endpoints were incidence of postoperative ileus (POI) and incidence of postoperative nausea and vomiting (PONV). The median time to first defecation was 62.5 h [45.8–80.8] in the OFA group and 118.5 h [82.6–142.3] (p< 0.001) in the control group. With regard to POI (OFA group: 1/22 patients (4.5%); control group: 2/22 (9.1%)) and PONV (OFA group: 5/22 patients (22.7%); control group: 10/22 (45.5%)), trends but no significant results were found (p= 0.99 andp= 0.203, respectively). OFA appears to be feasible in ORC and to improve postoperative functional gastrointestinal recovery by halving the time to first defecation compared with standard fentanyl-based intraoperative anesthesia.