Serum biomarkers that reflect the complex pathways of cancer progression have contributed to the clinical understanding of many malignancies. Recent studies have suggested that certain neuroendocrine (NE) elements participate in prostate cancer (PCa) progression. Interleukin-6 (IL-6) may serve as a useful marker of and contribute to PCa morbidity. The purpose of this study was to assess the frequency of elevation of two NE factors, chromogranin A (CGA) and bombesin-like immunoreactivity (BLI), in patients with advanced PCa and to determine their relationship to serum prostate-specific antigen PSA) and IL-6 levels, as well as known prognostic indicators (hormonal state, stage). Serum CGA determined by radioimmunoassay was elevated in I (7%) of 15 androgen-dependent (AD) patients and II (52%) of 21 androgen-independent (AI) patients; and urine BLI determined by radioimmunoassay was elevated in 2 (13%) of 16 AD patients and 10 (39%) of 21 AI patients. Frequency of elevation was higher in patients with distant metastasis (bone, visceral) compared with those with local/regional extensions of the disease. Levels of the NE factors correlated well with serum and bone marrow aspirate IL-6 concentrations but not with serum PSA levels. Elevation in either NE factor predicted for shortened survival. Measurement of NE factors in PCa identifies a subset of patients with advanced disease likely to express high levels of IL-6 and have a shorter survival. If confirmed, these findings will support the existence of a clinically relevant subset of patients in whom NE factors are involved in AI PCA progression.