Fascin-1, the most expressed form of fascin in vertebrate tissues, is an actin-bundling protein that induces cell membrane protrusions and increases motility of normal and transformed epithelial cells. Very few data are available on the role of this protein in nonsmall cell lung cancer (NSCLC). Two hundred and twenty patients with stage I NSCLC and long-term follow-up were evaluated immunocytochemically for fascin expression. Overall, variable fascin immunoreactivity was detected in 98% of 116 squamous cell carcinomas, in 78% of 96 adenocarcinomas, in 83% of six large cell carcinomas, and in the two adenosquamous carcinomas under study. Neoplastic emboli were commonly decorated by the antifascin antibody (P< 0.001), also when the surrounding invasive carcinoma was unreactive. Fascin immunoreactivity correlated with high tumour grade (P= 0.017) and, in adenocarcinomas, with high Ki-67 labelling index (P= 0.021). Adenocarcinomas with a prevalent bronchiolo-alveolar in situ component were less commonly immunoreactive for fascin than invasive tumours (P= 0.005). Contralateral thoracic or distant metastases were associated significantly with diffuse (> 60% immunoreactive tumour cells) fascin expression in adenocarcinomas (P= 0.043), and marginally with strong fascin immunostaining in squamous cell carcinomas (P= 0.13). No associations were noted with any other clinicopathological variables tested. Patients with tumours showing diffuse (> 60% immunoreactive neoplastic cells) and/or strong immunoreactivity for fascin had a shorter survival (P= 0.006 for adenocarcinomas and P= 0.026 for squamous cell carcinomas), even after multivariate analysis (P= 0.014 and 0.050, respectively). The current study documents for the first time that fascin is upregulated in invasive and more aggressive NSCLC, being an independent prognostic predictor of unfavourable clinical course of the disease. Targetting the fascin pathway could be a novel therapeutic strategy of NSCLC.