Following radical cystectomy (RC), µ-opioid-receptor antagonists have routinely used as part of enhanced recovery after surgery (ERAS) pathways because of their ability to decrease postoperative ileus and shorten the length of stay (LOS). Although alvimopan was utilized in previous research, the comparable medicine naloxegol is far more affordable. Researchers analyzed whether individuals who had RC and were given alvimopan or naloxegol fared better in the postoperative period. The conventional practice at the institution shifted from alvimopan to naloxegol over the course of 20 months. During that time, they kept all other aspects of the ERAS pathway the same and performed a retrospective analysis of all patients who underwent RC. Return of bowel function, ileus rates, and LOS after RC were compared using bivariate comparisons, negative binomial regression, and logistic regression. Alvimopan was given to 59 (50%), and naloxegol was given to 58 (50%) of 117 patients who were eligible for both drugs. None of the preoperative, intraoperative, or preexisting clinical, demographic, or socioeconomic variables were different. The median time to recovery after surgery was also 6 days (P=0.3) for both groups. In both the alvimopan and naloxegol groups, the time to flatus was identical (2 days for both, P=0.2), and the incidence of ileus was comparable (14% for both, P=0.6). When other patients and surgical characteristics were considered, a µ-opioid antagonist drug was not found to affect LOS or ileus in multivariable models. The average daily savings with naloxegol was $344.20, which amounted to a total of $2,065.20 over a 6-day hospital stay. There were no differences in postoperative recovery between patients having RC who was handled using a regular ERAS pathway and those who were given either alvimopan or naloxegol. Naloxegol could be a cost-effective alternative to alvimopan with the same clinical effects at a fraction of the price.