Chromogranin A is a useful probe of neuroendocrine neoplasia in humans. Here we optimize a rapid, sensitive radioimmunoassay modification for detecting chromogranin A in humans and other species. The site of chromogranin A circulation is the acellular plasma; platelets contain no chromogranin A immunoreactivity. The immunoreactivity in plasma is stable to repeated freezing and thawing, prolonged incubation at 37 degrees C, and lyophilization. Venipuncture alone resulted in modest (+ 12%, P less than 0.03) increase in chromogranin A in plasma. Several classic neuroendocrine neoplasia-pheochromocytoma, carcinoid tumor, neuroblastoma, and (vasoactive intestinal polypeptide)oma-produce markedly increased chromogranin A in plasma. By contrast, subjects with malignant melanoma, renal cell carcinoma, and thymoma all had normal values for chromogranin A. Hypersecretion of human choriogonadotropin beta subunit from both malignant (choriocarcinoma) and normal (placenta) syncytiotrophoblast cells was unaccompanied by an increase in chromogranin A, a dissociation compatible with the lack of granular storage and release of syncytiotrophoblastic peptide hormones. Both hepatic and renal failure resulted in increased chromogranin A in plasma, with renal failure leading to concentrations otherwise seen only in neuroendocrine neoplasia. These observations refine the diagnostic specificity of chromogranin A in plasma.