Immunohistochemical expression of p53, bcl-2, CD44 standard (CD44S), and the v6 isoform of CD44 (CD44v6) proteins were studied in 14 typical carcinoid tumors (TCs), 11 atypical carcinoids (ACs), and eight small cell carcinomas (SCLCs) in an attempt to use these markers of mutational events and cellular adhesion to discriminate neoplasms demonstrating neuroendocrine differentiation. p53 and bcl-2 overexpression were associated with more aggressive neuroendocrine cell types. p53 nuclear staining was weakly positive in 21% of the TCs, whereas strong nuclear staining was seen in 64% of the ACs and 88% of the SCLCs (P = 0.0047). bcl-2 was present in 21% of the TCs, 91% of the ACs, and 100% of the SCLCs (P = 0.0001). In contrast, CD44S and CD44v6 were inversely correlated with more aggressive types of neuroendocrine tumors. CD44S expression was moderate to strong in all of the TCs and 91% of the ACs but in only 37% of the SCLCs (P = 0.0018). There was no correlation between expression of these markers and tumor size or nodal status, although loss of CD44v6 was associated with lymph node metastases in the TC group only. In the spectrum of neuroendocrine tumors of the lung, p53 and bcl-2 overexpression correlates with more aggressive histologic cell types. The decreasing CD44S expression in AC and SCLC is similar to findings in cancer of the colon and in non-small cell carcinoma of the lung, where loss of CD44S is associated with poor prognosis. In AC and SCLC, but not in cancer of the colon, loss of CD44v6 correlates with more aggressive neoplasms and might correlate with lymph node metastases in TCs.