USP17 is a cell cycle regulated deubiquitinating enzyme that is highly expressed in tumor-derived cell lines and has an established role in cell proliferation and chemotaxis. This is the first study to examine the clinical significance of USP17 expression in non-small cell lung cancer (NSCLC). USP17 was overexpressed in both squamous and adenocarcinoma NSCLC tissue. Patients with USP17 positive tumors had significantly reduced recurrence-free survival than patients with USP17 negative tumors. Moreover, USP17 was more highly expressed in patients with recurrence of disease at distant sites, suggesting that USP17 levels may correlate with NSCLC distant metastases. Overall, these findings establish USP17 as a potentially valuable novel biomarker for metastatic lung cancer.