CD44 is an integral membrane glycoprotein that functions as a receptor for the extracellular matrix glycan, hyaluronan. Here we report that CD44 is a novel biomarker for non-small cell lung tumors, squamous metaplasia of the lung, and activated type II pneumocytes. We have examined the expression of CD44 in 12 human lung tumor cell lines and 23 fixed, paraffin-embedded lung cancers. CD44 transcription and translation is consistently high among non-small cell tumors (5 of 5 cell lines, 10 of 14 tumors) but rare in small cell tumors (1 of 6 cell lines, 0 of 9 tumors). In normal lung, CD44 was confined to the surface of bronchial basal cells and alveolar macrophages. Squamous metaplasia of the lung showed strong CD44 immunoreactivity. Resting type II pneumocytes were largely CD44 negative but rows of active, surfactant-secreting type II cells had significant amounts of CD44 located on lateral surfaces of adjacent cells. The correlation between CD44 and the non-small cell phenotype was further demonstrated in studies of a cultured small cell lung cancer line induced to exhibit characteristics of a non-small lung cancer by infection with v-Ha-ras. Following ras gen insertion, these cells showed a 40-fold increase in CD44 expression. The CD44 detected in lung cancer cells throughout these studies was predominantly the "standard" rather than the "variant" species. Taken together, these results suggest that CD44 is a protein expressed on non-small cell lung tumors, squamous metaplasia, and activated type II cells. In addition, CD44 in cultured small cell lung cancer cells is transcriptionally activated following differentiation by the ras oncogene. The fact that immunohistochemistry can be used to discriminate among the cell types makes CD44 a valuable new marker for lung neoplasia.