BACKGROUND: Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs). PATIENTS AND METHODS: We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n = 283; 45, other subtypes (n = 95; 15, micropapillary (n = 85; 14, adenocarcinoma (n = 65; 10, small cell (n = 54; 8.6, and sarcomatous (n = 47; 7.6. Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV. RESULTS: Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n = 44; 9.8 had had worse CSS (median CSS, 33 vs. 116 months; P textless .001) and higher mortality rates (hazard ratio, 2.1; P = .03) compared with those with pure UC (n = 328; 72.9. The results of the analyses were also confirmed when the pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed a lower rate of clinical-to-pathologic downstaging (odds ratio, 0.4; P = .03) compared with UC. CONCLUSIONS: SCC was the HV exhibiting the lowest effect of NAC in terms of activity and CSS. Compared with pure UC, SCC seemed to be insensitive to traditional NAC regimens.