Small cell lung cancers (SCLCs) and non-small cell lung cancers (NSCLCs), two major categories of human lung cancers, have been shown to exhibit considerably different clinicopathological, biological, and molecular genetic characteristics. Inactivation of cyclin-dependent kinase inhibitors is now thought to play an important part in the pathogenesis of this fatal disease. In the present study, we show that in vitro p27KIP1 expression was associated with cell density-dependent growth inhibition in human lung epithelial cells in vitro, whereas in vivo, p27KIP1 expression in lung cells showed an inverse correlation with proliferative activity in the developing and adult normal lungs. Our immunohistochemical examination of 166 lung tumor specimens also revealed a striking difference in p27KIP1 expression between SCLCs and NSCLCs. Of 149 NSCLCs, 107 (72%) showed reduced p27KIP1 expression, with 8 being virtually negative. Furthermore, p27KIP1 expression status was found to be a significant prognostic factor for patient survival in the analysis of the 149 primary, resected NSCLC cases (P = 0.03 by the log-rank test). In contrast, all SCLC specimens thus far examined exhibited significantly increased staining when compared to the corresponding normal lung epithelium. These findings provide additional evidence for the heterogeneity prevalent in human lung cancers and suggest that p27KIP1 might play distinct biological roles in the pathogenesis of the two major histological categories, warranting additional studies to elucidate the functional consequences of such differences.