Sarcomatoid differentiation is a rare variant of urothelial carcinoma (UC) seen in 0.6% of cases. Its response to neo-adjuvant chemotherapy (NAC) has not been well reported. The authors have done a retrospective analysis of patients undergoing cystectomy between 1995 and 2018 to compare outcomes of patients with sarcomatoid histology to UC not otherwise specified (UC, NOS). One hundred and thirty-one patients with sarcomatoid differentiation and 1722 patients with UC, NOS were identified. The outcomes evaluated were response to NAC, association with worse disease characteristics and survival rates. Patients with sarcomatoid histology were more likely to receive NAC (29% vs. 18%; P=0.003) and had a higher T-stage (94% ≥ T2 vs. 62%; P<0.001). Three hundred and thirteen patients with UC, NOS and 25 patients with sarcomatoid differentiation received NAC. A cisplatin-based regimen was used in 93% and 92% of patients with UC, NOS and sarcomatoid differentiation, respectively. The response rates between the two groups showed no significant difference (P=0.6) with complete response in 24% vs. 20% and partial response in 31% vs. 24% in UC, NOS and sarcomatoid differentiation, respectively. Post-hoc analysis showed that timing of diagnosis of variant histology may be a factor. Sarcomatoid histology was associated with worse recurrence-free (45% vs. 71%, P<0.001), cancer-specific (51% vs. 75%, P<0.001) and overall survival (45% vs. 63%, P<0.001). Adjusting for other variables, sarcomatoid histology was identified to have worse recurrence-free (HR 1.82, 95% CI 1.39-2.39, P<0.001) and cancer-specific survival (HR 1.66, 95% CI 1.23-2.22, P<0.001). Among patients with sarcomatoid histology, recurrence-free survival at five years for patients who received NAC was 55% compared to 40% among those who did not (P=0.1). Based on their findings of 20% complete response to NAC and improved survival, the authors recommend the use of NAC for sarcomatoid histology detected on transurethral resection. Given the significantly worse outcomes, they note the need for research in identifying more effective therapeutic strategies.