INTRODUCTION: Among the measures taken in the recent years to reduce the morbidity and improve functional recovery after radical cystectomy (RC), the optimization of perioperative care pathways is gaining a prominent role. The aim of this systematic review of the literature with meta-analysis is to assess the impact of enhanced recovery after surgery (ERAS) protocols vs. standard of care on perioperative outcomes of patients undergoing RC. EVIDENCE ACQUISITION: A systematic review with meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. MEDLINE, SCOPUS and Web of Science databases were searched. Only comparative studies evaluating the impact of ERAS protocols vs. standard of care on intraoperative and postoperative outcomes of patients undergoing RC were included. Cumulative analysis was conducted using Review Manager v.5.3 software. Statistical heterogeneity was tested using the χ2 Test, and a P value <0.10 was used to indicate heterogeneity. Random-effects and fixed-effects models were used as appropriate depending on heterogeneity status. EVIDENCE SYNTHESIS: A total of 27 studies were included, namely 3 randomized and 24 non-randomized controlled studies, resulting in 4712 patients, 2690 (57%) participants to some ERAS protocol and 2022 (43%) controls receiving standard of care. A number of primary and secondary outcome measures were assessed in the original studies. Pooled data showed that ERAS protocols were associated with significantly faster recovery of bowel function, faster return to regular diet and shorter hospital stay with no increase in 30-day and 90-day major complication, mortality or readmission rates compared to standard of care. The magnitude of benefit of the various ERAS protocols tested had, however, a non-negligible inter-study variability. CONCLUSIONS: This systematic review with meta-analysis of comparative studies showed that ERAS protocols applied to patients undergoing RC enabled a faster recovery of bowel function, a faster return to regular diet and a shorter hospital stay with no increase in major complication or readmission rate compared to standard perioperative care. RC with ERAS protocols should be considered the new standard of care.