UNLABELLED We assessed 126 patients with cT1-4, N0-2 urothelial carcinoma of the bladder who were treated with neoadjuvant chemotherapy followed by radical cystectomy. Twenty patients (16%) had squamous or glandular histological variation (HV). Significant pathologic downstaging (pT<2, N0) was seen in the HV patients (60% vs. 32%; P [ .02) and this difference remained significant after controlling for other clinical and pathological confounders. BACKGROUND To assess the pathological response rates and survival outcomes in patients with squamous or glandular histological variation (HV) treated with neoadjuvant chemotherapy (nCT) and radical cystectomy (RC), and compare these with patients with pure urothelial carcinoma of the bladder (PUCB). PATIENTS AND METHODS We performed a retrospective review of patients with clinical stage T1-4, N0-2 urothelial cancer treated with cisplatin-based nCT and RC in a single institution setting. Patients who received neoadjuvant carboplatin-based regimens were excluded. The primary end point was pathological response. Overall survival (OS) was a secondary end point. Logistic regression and Cox proportional hazard models were used for multivariate analyses. RESULTS We evaluated 126 patients, including 20 (16%) with HV. Median estimated glomerular filtration rate (79.6 vs. 73.6 mL/min; P = .07) and the rate of complete endoscopic resection (75% vs. 40%; P = .01) were higher in the HV patients. Complete pathological response was similar between the groups (21% PUCB vs. 25% HV; P = .77). However, a significantly higher rate of pathologic downstaging (pT<2, N0 [pDS]) was seen in the HV patients (60% vs. 32%; P = .02). In a logistic regression model to predict pDS, in which clinically relevant confounding variables were included, HV (odds ratio, 4.01; 95% confidence interval, 1.16-13.9) remained an independent predictor of pDS. OS was similar between the 2 groups (HV: 45.7 vs. PUCB: 48.3 months; P = .73). CONCLUSION When controlling for confounding factors, improved pDS rates were seen in the HV patients although there were no significant differences in the OS stratified according to histology. These results support the continued use of systemic nCT for this subgroup of patients.