Objective: We aimed to analyze the phosphatases of regenerating liver 1 (PTP4A1) expression and its relationship with tumor invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC). Methods: The retrospective study enrolled 150 cases who underwent radical resection for primary NSCLC during the period from January 2006 to January 2014. Baseline characteristics of patients included age, gender, smoking history, pathological type, histological grade, clinical stage, and lymphatic metastasis. Lung cancer tissues collected from 150 cases and precancerous tissues, and normal lung tissues collected from 20 cases were used for PTP4A1 detection by immunohistochemistry. Results: The expression of PTP4A1 was significantly different in different tissue samples (P = 0.025). The expression level of PTP4A1 was associated with clinical stage (P = 0.022), and lymphatic metastasis (P = 0.011). Survival analysis showed the total survival rate of overexpressed PTP4A1 group was significantly lower than that of the low expressed PTP4A1 group (P = 0.006), while the recurrence rate of overexpressed PTP4A1 was significantly higher than that of the low expressed PTP4A1 group (P = 0.014). In addition, the OS was affected by lymphatic metastasis, and disease-free survival was influenced by pathological type and lymphatic metastasis. Conclusion: The PTP4A1 expression level is a potential prognostic biomarker for NSCLC, and overexpression of PTP4A1 suggested a high risk of poor DFS during follow-up. Also, lymphatic metastasis had an adverse effect on survival time.