We examined retrospectively 107 step-sectioned radical prostatectomy specimens. The index tumor in each specimen was designated a transition zone carcinoma (TZCa) or a peripheral zone carcinoma (PZCa) based on its location. Ah tumor sections were immunohistochemically stained with chromogranin A (ChrA). A semiquantitative ChrA score (0 to 3) was assessed. ChrA-positive neuroendocrine cells were found in 83% of the index tumors. The ChrA score was significantly related to the Gleason score, the volume of the tumor, and the pathologic stage. Twenty-two percent of the index tumors were designated TZCas; 75% of these demonstrated neuroendocrine differentiation versus 85% of the PZCas. A high ChrA score of greater than or equal to 2 was found in 46% of PZCas and in only 33% of TZCas. Capsular transgression, seminal vesicle involvement, positive surgical margins, and lymph node metastasis were seen in the TZCa group in 33%, 17%, 29%, and 4%, respectively versus 58%, 20%, 48%, and 6% in the PZCa group. These findings were associated with a higher mean tumor volume in the TZCa group compared with the PZCa group. The average Gleason score of 4.5 in the TZCa group was significantly (P < 0.0001) lower than the Gleason score 6.2 in the PZCa group. Multicentricity was found in 62% of TZCas and in 49% of PZCas. Eighty-seven percent of the second tumors in the prostates with a primary TZCa were located in the peripheral zone. We conclude that the frequently occurring neuroendocrine cells population enlarges with tumor progression, especially in PZCas. The lower incidence of capsular transgression, seminal vesicle involvement, positive surgical margins, and lymph node metastasis together with the generally better degree of differentiation may indicate an overall better prognosis for TZCas. Nevertheless, it is possible that the final outcome for the individual patient with a primary TZCa may be influenced by the frequently occurring secondary PZCa.