Neuron-specific enolase (NSE), an isomer of glycolytic enzyme enolase, is found exclusively in neuroendocrine cells and in neuroendocrine tumors in a considerably large quantity. Circulating levels of serum NSE were measured by radioimmunoassay in 24 normal adults, 23 patients with benign pheochromocytoma, three patients with malignant pheochromocytoma, and seven patients with medullary thyroid carcinoma. The mean serum NSE in normal adults was 5.8 +/- 1.3 ng/ml (mean +/- standard deviation [SD], and the range was 3.8 to 8.9 ng/ml). It also was normal in patients with benign pheochromocytoma (5.7 +/- 1.8 ng/ml; range, 2.2 to 9.3 ng/ml). However, serum NSE was elevated significantly (17.2 +/- 7.2 ng/ml; range, 10.4 to 27.3 ng/ml) in all three patients with malignant pheochromocytoma (P less than 0.01). In patients with medullary thyroid carcinoma the serum NSE remained within normal limits (5.5 +/- 1.7 ng/ml; range, 3.9 to 8.2 ng/ml). These results suggest that serum NSE might be a useful marker for screening of malignant pheochromocytoma.