It has been documented that changes in the histopathologic subtype of small cell carcinoma of the lung (SCCL) may occur after chemotherapy. The significance of such changes with respect to response to treatment has not yet been studied. In a retrospective review of 25 patients, we correlated their response from chemotherapy with morphologic changes seen in subsequent histologic material. Eleven patients responded to therapy and 14 failed to respond. A difference in original histologic subtype was found in 10 (71%) of the nonresponders and in only two (18%) of the responders. The difference was statistically significant (p less than 0.05). We conclude that patients with "pure" SCCL in the initial biopsy specimen who fail to respond to chemotherapy are likely to have mixed or combined histologic subtypes in subsequent tissue specimens, although we cannot preclude their pre-existence. An attempt to search for different histologic subtypes is warranted in patients who do not respond to chemotherapy regimens considered to be efficacious in SCCL.