Neuroendocrine lung tumors have been considered by some to be a continuum ranging from relatively benign typical carcinoids to highly malignant small-cell carcinomas. Histopathological diagnosis may sometimes be difficult because of their overlapping features. Correct classification, however, carries important prognostic and therapeutic significance. To determine the clinicopathological implications of retinoblastoma (RB) protein expression in these neoplasms, we examined the RB status in a series of neuroendocrine tumors by immunohistochemical analysis of paraffin-embedded tissue sections. A total of 105 tumors were studied. All 44 typical and 15 atypical carcinoids, one of which was initially misdiagnosed as a small-cell carcinoma, manifested a heterogeneous RB-positive staining pattern. Atypical carcinoids in general showed an increase in the number of tumor cells with strong nuclear staining compared to typical carcinoids. In contrast, all 40 small-cell and 6 large-cell neuroendocrine carcinomas failed to show RB staining in any tumor nuclei, indicating loss of RB function. Our results suggest that RB status as measured by immunohistochemical staining can be used as a marker to distinguish typical and atypical carcinoids from small-cell and large-cell neuroendocrine carcinomas.