Epidemiological studies indicate that the use of aspirin decreases incidence of and mortality from gastrointestinal cancers. A major target of aspirin and other nonsteroid anti-inflammatory drugs is cyclooxygenase (Cox), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. Two Cox genes have been cloned (Cox-1 and Cox-2), of which Cox-2 has recently been found to be expressed in several human carcinomas. We have now studied the expression of Cox-2 mRNA and protein in human lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer. Cox-2 mRNA steady-state levels were high in well-differentiated adenocarcinoma samples, but low in poorly differentiated adenocarcinoma, squamous cell carcinoma, and small cell lung cancer, as detected by Northern blot analysis. Immunohistochemistry showed Cox-2 staining in 19 of 21 adenocarcinomas. However, well-differentiated adenocarcinomas contained more Cox-2 staining than the poorly differentiated ones. Expression of the Cox-2 protein was also seen in all 11 squamous cell carcinomas studied, although the level of staining seemed to be less than that in the adenocarcinomas. Small cell lung cancer specimens (n = 4) stained with a relatively weak intensity. Interestingly, atypical alveolar epithelium, which associates with asbestosis and idiopathic fibrosing alveolitis and is considered to be a precursor lesion for lung cancer, expressed the Cox-2 protein. Our data, thus, suggest that Cox-2 is expressed in human lung carcinomas and in precursor lesions leading to this malignancy.