Background: Neoadjuvant chemotherapy (NAC), often with a cisplatin-based regimen, is recommended before radical cystectomy (RC), as studies have shown a modest survival benefit. However, NAC may confer toxicity and augment preoperative frailty, affecting perioperative outcomes. We investigated the relationship between NAC and 30-day RC outcomes using the National Surgical Quality Improvement Program (NSQIP). Methods: RCs performed between 2019-2020 were identified in NSQIP and the corresponding cystectomy-targeted database. Baseline demographics, comorbidities, and operative parameters were compared via Pearson’s chi-square and t-tests between patients who received NAC before RC and RC alone (RCA) groups. Patient frailty was compared using the NSQIP frailty index (mFI-5), a validated 5-item score including points for diabetes, functional status, chronic obstructive pulmonary disease, heart failure, and hypertension. Multivariable logistic regression was used to compare outcomes, adjusting for age, race, robotic or open approach, urinary diversion type, comorbidities, ASA classification, and functional status. Minor complications included superficial SSI, pneumonia, UTI, bleeding requiring transfusion, AKI, or C.diff infection. Major 30-day complications included sepsis, DVT, stroke, reintubation, renal failure, MI, PE, septic shock, wound dehiscence, deep wound infection, cardiac arrest, readmission, reoperation, or mortality. All statistical tests were two tailed, p<0.05 considered significant. Results: 4,482 RCs were identified. Of these, 1889 (42%) patients received NAC. Compared to RCA, NAC patients were younger (66.9 years vs 70.4 years, p<0.001), had higher rates of white race, being functionally independent, preoperative weight loss, and cigarette use. NAC also had lower ASA class, fewer comorbidities, and lower frailty (mFI-5 0.8 vs 0.9, p<0.001). Compared to RCA, NAC patients had more robotic cystectomies (23% vs 19%, p=0.0003), received more continent diversions, had a shorter length of stay (7.1 vs 7.8 days, p<0.001), and more commonly had pT0 tumors compared to RCA (18.4% vs 5.9%, p<0.001). On MVA, NAC patients had higher rates of minor complications, most notably increased bleeding requiring transfusion [OR 1.8; 95%CI 1.6-2.1; p<0.001]. There was no difference in major complications between NAC and RCA, except NAC was associated with higher rates of sepsis [OR 1.4; 95%CI 1.1-1.8; p=0.003]. There was no difference in 30-day need for reoperation, readmission, or mortality. Conclusions: In the largest study to date on this topic, we found that NAC for RC is often given to younger, healthier patients, and is not associated with higher rates of major complications or mortality. NAC is associated with higher rates of bleeding and sepsis, which may be related to the immunosuppressive effects of chemotherapeutics. Providers should discuss with patients the benefits and risks of NAC before RC.