Background: Psoriasin (S100A7) is a member of the S100 gene family. Alteration of Psoriasin expression has previously been reported to play an important role in cancer aggressive behaviour. The current study sought to investigate the level of Psoriasin expression at the mRNA level in a cohort of patients with non-small cell lung cancer (NSCLC), the association with clinical implication and outcomes, and the molecular and cellular impact of the protein on lung cancer cells. Methods: Fresh frozen NSCLC cell carcinoma tissues, along with matched normal tissues were obtained from 83 NSCLC patients who received curative resection from January 2003 to December 2011. The expression of Psoriasin in the NSCLC specimens was assessed using both quantitative real time PCR (QPCR) and immunochemical staining. Knockdown and forced expression of Psoriasin in NSCLC cell lines were carried out using constructed plasmid vectors carrying either ribozyme transgenes targeting human Psoriasin or full-length coding sequence, respectively. The effect of Psoriasin on the functions of NSCLC cells was determined using a variety of in vitro cell function assays. Results: Higher mRNA levels of Psoriasin were observed in tumour tissues when compared to both the paired normal background tissues and none paired normal tissues (p = 0.0251 and 0.0195). The mRNA level of Psoriasin was found to be higher in the squamous carcinoma (P = 0.035). Higher Psoriasin expression is associated with poor prognosis. The cell function tests had supportive results to the clinical findings. Over-expression of Posriasin in lung cancer cells (SK-MES-1) resulted in an increase in in vitro growth and invasiveness. In contrast, Psoriasin knockdown suppressed cell growth and invasion (P<0.05), but increased cell adhesion (P<0.05). Conclusions: Psoriasin expression is increased in lung cancer, more specifically in lung squamous carcinoma compared with adenocarcinoma, and is associated with poor prognosis. Psoriasin plays crucial roles in regulating the growth and invasion of lung cancer cells.