Twelve large cell carcinomas of the lung showing evidence of neuroendocrine differentiation (LCCND) were compared with 15 other large cell pulmonary tumors that lacked such features (NELCUC). All lesions were composed of partially necrotic, nested, or sheet-like arrays of mitotically active, nucleolated large cells that were at least twice the size of those seen in small cell carcinomas. Examples of LCCND were defined by immunoreactivity for neuron-specific enolase, Leu-7, synaptophysin, and chromogranin-A, and by their content of neurosecretory granules on electron microscopy. NELCUCs were devoid of these immunohistologic and ultrastructural features. There were six women and six men with LCCND, who ranged in age from 38 to 82 years. Of nine individuals in this group with Stage T1NOMO or T2NOMO disease at diagnosis, five (55%) died of their neoplasms within 3 years of diagnosis; three more (33%) have recurrent or persistent tumors and are likely to die as a result. On the other hand, 47% of patients with NELCUC of similar stages are free of disease after a similar follow-up period. LCCND is a distinctive clinicopathologic disease and should not be classified with unspecified large cell anaplastic carcinomas of the lung. Its behavior is potentially aggressive and may justify consideration of a specialized treatment protocol. Because electron microscopic evaluation of immunohistologic features must be done to recognize LCCND, it is probably underdiagnosed.