Small cell carcinoma of prostate is rare, with the literature consisting of case reports and small series. The current work analyzes the morphology and immunohistochemistry of 95 cases of prostatic small cell carcinoma diagnosed at our institution. Specimens included 55 needle biopsies, 27 transurethral resections, 4 radical prostatectomies, and 9 biopsies from metastatic sites (some patients with >1 procedure). Patients ranged in age from 44 to 92 years old (mean: 69 y). Although serum prostate-specific antigen (PSA) in some cases was very high (up to 1896 ng/mL), the median value was only 4.0 ng/mL. Of cases with available information, 33/78 (42%) had a history of usual prostatic adenocarcinoma. The interval between the diagnosis of small cell carcinoma and prior usual prostatic cancer ranged from 1 to 300 months (median 25 mo). Pure small cell carcinoma was seen in 54/95 (57%) of cases with the remaining cases admixed with prostate adenocarcinoma. In cases with adenocarcinoma, there was a sharp demarcation between small cell carcinoma and adenocarcinoma in 20.5% of cases; in the remaining cases there was gradual merging of the 2 components. In mixed cases, small cell carcinoma predominated (median: 80% of the tumor); the Gleason score of the adenocarcinoma was > or =8 in 85% of these cases. In 61 cases (64%), small cell carcinoma was classic "oat cell" morphology with remaining the "intermediate cell" variant. Of the 95 cases: necrosis was seen in 40% (2% to 95% of the tumor); giant bizarre cells in 19%; Indian filing in 21%; rosette formation in 29%; focal vacuolated cytoplasm in 18%; and desmoplasia in 20%. Most (88%) of small cell carcinoma were positive for at least 1 neuroendocrine marker. In the small cell carcinoma component, 14/73 (19%) were positive for PSA, 17/61 (28%) positive for prostein (P501S), and 15/59 (25%) positive for prostate-specific membrane antigen, although often very focally. Stains for thyroid transcription factor-1 were positive in 23/44 (52.3%) cases. In this, the largest study of prostatic small cell carcinoma, we highlight the presence of morphologic features that may result in its underdiagnosis. Other more classic histologic features of small cell carcinoma along with rosettes are critical for its accurate diagnosis. P501S and prostate-specific membrane antigen were better in identifying the prostatic origin of small cell carcinoma than PSA, although the majority (60%) of prostatic small cell carcinomas were negative for all 3 markers.