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Neutrophil-to-lymphocyte ratio (NLR) might reflect an increased neutrophilic inflammatory response, and urothelial tumors with squamous-cell features (SqD) have been linked to inflammation. We hypothesized that NLR could be prognostic in these patients.In patients with SqD muscle-invasive bladder cancer treated with curative intent, NLR and relationships with outcomes were analyzed by Cox regression, log-rank, and Kaplan-Meier analysis.Fifty patients presented SqD (median follow-up, 29 months). The ideal NLR cutoff (by receiver operating characteristic curves) was 5. Thirty-seven patients had NLR < 5 and 13 had NLR ≥ 5. The 5-year progression-free survival, cancer-specific survival (CSS), and overall survival were 46.8%, 48.4%, and 45% for NLR < 5 cases, and 10.3%, 10.3%, and 11.7% for NLR ≥ 5 cases (all P < .05). On multivariate analysis, NLR was prognostic (hazard ratio = 4.26, 6.21, and 4.08 for progression-free survival, CSS, and overall survival). Neoadjuvant chemotherapy (NAC) was of significant benefit in NLR < 5 patients, with a CSS of 91.2 months (n = 3) versus 38.1 months (n = 24) for those treated with up-front radical cystectomy (P = .009); Kaplan-Meier curves were also significantly different. These differences did not reach statistical significance for patients with NLR ≥ 5. For the 19 patients treated with NAC, NLR was also predictive of response to NAC.Inflammation, measured by NLR, is potentially prognostic in the perioperative management of SqD. NLR identifies 2 risk groups. Patients displaying low NLR had a 4-fold survival improvement and were highly responsive to NAC. NLR might be a good prognostic tool. Its role as a predictor of response to NAC deserves future study, along with its role as a selection criterion for therapies other than chemotherapy.Squamous-cell features in bladder cancer, which have been linked to chronic inflammation, represent a challenge to providers and patients because these tumors tend to be chemorefractory. We provide evidence that neutrophil inflammation, measured with peripheral blood levels of neutrophil-to-lymphocyte ratio as a surrogate, is linked to prognosis with patients displaying low NLR showing a 4-fold survival outcome and being highly responsive to neoadjuvant chemotherapy.