Squamous cell carcinoma of the bladder comprises less than 5% of all bladder cancers in the United States and its long-term prognosis has remained controversial. We examined a large series of patients who underwent radical and partial cystectomies for squamous cell carcinoma to identify associated histopathologic findings and clinical outcomes associated with these tumors. Patient age ranged from 46 to 83 years (average 68.5 y) with a male:female ratio of 3:2. Forty-three patients were white and 2 patients were African-American. No patient had a history of schistosomal infection and only 1 patient had a history of condyloma acuminatum. The majority of patients with reported signs and symptoms presented with hematuria (n=29/34), with the remainder presenting with lower urinary tract symptoms. Tumor size ranged from 0.8 to 6.4 cm (average 3.8 cm). Invasion was identified into the lamina propria (pT1, n=1/45), muscularis propria (pT2, n=14/45), perivesical fat (pT3, n=27/45), and adjacent structures (pT4, n=3/45). Concurrent metastases were identified in 11 of 45 patients (24%) to pelvic lymph nodes (n=9), perivesical lymph nodes (n=3), obturator lymph nodes (n=1), and bowel wall (n=1). Most tumors were moderately (n=29/45) or poorly (n=13/45) differentiated, whereas only 3 tumors were well differentiated (n=3/45). Keratinization was present in all cases within the invasive component and ranged from 5% to 95% of tumor bulk. Necrosis ranged from 0% to 60% and inversely correlated with tumor differentiation. Eighteen cases demonstrated a prominent giant cell reaction to keratin, and 30 tumors were associated with a desmoplastic reaction. Extensive perineural (n=11/45) and angiolymphatic invasion (n=7/45) were identified in a subset of tumors. The majority of cases demonstrated associated superficial lesions including keratinizing squamous metaplasia (n=28/45), nonkeratinizing squamous metaplasia (n=20/45), squamous cell carcinoma in situ (n=16/45), squamous metaplasia with dysplasia (n=4/45), verrucous squamous hyperplasia (n=3/45), and extensive condyloma acuminatum (n=1/45). Seven cases additionally demonstrated separate small foci of focal flat urothelial carcinoma in situ. Three cases demonstrated a markedly atypical squamous lining of the prostatic ducts at the prostatic urethra. Clinical follow-up was available on 35 patients (78%) and ranged from 1 to 175 months (average 33 mo, median 15 mo). Two patients developed recurrent local disease (n=2/35, 6%) and 13 patients developed subsequent metastatic disease (n=13/35, 37%). Ten patients were dead of disease (29%), with a time to death for most patients of less than 2 years (range 2 to 21 mo, average 10.5 mo). Thirty-seven percent of patients (n=13/35) were alive without disease. In conclusion, squamous cell carcinoma often presents at an advanced stage; however, radical cystectomy with lymph node dissection appears to offer a significant benefit in survival in a subset of patients.