PGP9.5 is a neurospecific peptide that functions to remove ubiquitin from ubiquitinated proteins and prevents them from targeted degradation by proteasomes. Using the serial analysis of gene expression method (SAGE), we observed that the PGP9.5 transcript was highly expressed in primary lung cancers and lung cancer cell lines but was not detectable in the normal lung. Here we examined the expression of PGP9.5 protein in normal lung epithelium, lung tumor cell lines, and 98 resected primary non-small-cell lung carcinomas (NSCLCs). We found PGP9.5 reactivity in normal lung in a pattern compatible with K-cells of the diffuse neuroendocrine system. However, the PGP9.5 was present in both small-cell lung cancer (SCLC) and NSCLC cell lines (22/24) independent of neuronal differentiation. In primary NSCLCs, 54% (53/98) of the cases had positive PGP9.5 staining, and the expression of protein was strongly associated with pathological stage of the cancer. It was present in 44% (29/66) of stage I NSCLCs and in 75% (24/32) of stage II and IIIA NSCLCs (p = 0.0032). These results suggest that the increased expression of PGP9.5 is specifically associated with lung cancer development and may serve as a potential marker for the detection of lung cancer.