The diagnosis of neuroendocrine neoplasms (NENs) may be challenging and is based on typical morphological features and positive staining for antibodies of neuroendocrine differentiation. Neuron-specific enolase (NSE) being a cytosolic marker may be useful in this setting. NSE is by many considered nonspecific, due to the finding of this marker in tumors considered not to be of neuroendocrine origin. Our aim was to determine whether this is true and whether NSE is more specific than previously realized. We examined 178 tumors (carcinomas and NENs) from breast, lung, stomach, and kidney using immunohistochemistry with the following markers: chromogranin A, synaptophysin, CD56, secretagogin, and NSE. Expression of NSE was compared with that of the other markers. NSE was expressed in 138 (78%) of all tumors. Of the NSE-expressing tumors, 95 (68%) cases expressed one or more additional neuroendocrine markers. The staining intensity and number of NSE-expressing tumor cells were highest among tumors of neuroendocrine origin and clear cell renal cell carcinomas. A positive association was found between NSE expression and the number of additional neuroendocrine markers expressed in each of the tumors. Practically all tumors positive for an accepted neuroendocrine marker also expressed NSE.