To better understand the clinical and pathologic features of end-stage, androgen-independent carcinoma of the prostate (CaP), we performed rapid autopsies on 14 men who died of progressive CaP and recorded relevant clinical data. The timing of tumor progression varied widely. The median time to androgen independence was 2 years (range, 4 months to 13.6 years). The median survival after androgen independence was 1 year (range, 1 month to 3.6 years). Because osseous metastases are prevalent in progressive CaP, up to 20 bone sites were systematically sampled in each patient. Bone metastases were widespread; tumor filled the marrow in an average of 14 bone sites. Tumor histology and expression of prostate-specific antigen (PSA) and chromogranin A (CGA) were examined in all metastases and were compared with the primary tumor. Five histological patterns of metastatic tumor were observed: solid (10 patients), macroacinar (1 patient), microacinar (1 patient), clear cell (1 patient), and comedocarcinoma (1 patient). Gleason grade of the primary tumor did not predict the histological pattern of the metastases. Although >70% of tumor cells expressed PSA, the fraction of PSA-positive cells varied widely in separate metastases in some patients (standard deviation >25). Likewise, the fraction of neuroendocrine (NE) (CGA-positive) tumor cells in different metastases varied widely. For example, between 0 and 95% of tumor cells in different metastases in 1 patient had a NE phenotype. The present study highlights the heterogeneity--histologically and immunophenotypically--of metastatic CaP. Consequently, therapy directed to the phenotype of 1 metastasis may have no effect on other metastases in the same patient because of phenotypic heterogeneity.