We evaluated the usefulness of L-dopa decarboxylase (DDC) as a tumor marker of neuroendocrine (NE) cell differentiation by measuring its expression in 432 human tumors of diverse types and origins. A subset of these tumors and cell lines derived from them also were studied for expression of two other general NE cell markers, chromogranin A (CgA) and dense core granules (DCG). High concentrations of DDC were present in 96 of 117 (82%) tumors recognized to be of NE or neural origin. As expected, endocrine tumors not recognized to be of NE cell origin, as well as leukemias, lymphomas, sarcomas, melanomas, and germ cell tumors, lacked DDC expression. Of interest, modest concentrations of DDC were present in 46 of 220 (21%) nonendocrine carcinomas, especially non-small cell lung and colorectal carcinomas. We studied concordant expression of the three NE cell markers in lung and colorectal tumors and cell lines. In both tumor types there was nearly 100% concordance between CgA and DCG expression. There was an excellent correlation between DDC and CgA expression in lung cancers, both small cell and non-small cell, but DDC positive colorectal carcinomas usually lacked CgA expression. We conclude: (a) DDC is an excellent cellular marker for tumors of the NE cell system; (b) about 20% of carcinomas not of NE cell origin, especially non-small cell lung and colorectal carcinomas, express DDC, suggesting a common endodermal origin of all of the respiratory and gastrointestinal mucosal cells; and (c) CgA and DCG are expressed concordantly, indicating that CgA expression may be used as a substitute for ultrastructural examination of tumors for DCG expression.