It has been reported that protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) plays an important role in cancer tumorigenesis. However, the clinical and functional significance of PPM1D expression has not been characterized previously in non-small cell lung cancer (NSCLC). The purpose of this study was to assess PPM1D expression and to explore its contribution to NSCLC. We examined PPM1D messenger RNA (mRNA) expression in 53 NSCLC tissues and matched adjacent noncancerous tissues by quantitative reverse transcription PCR (qRT-PCR). Furthermore, the PPM1D protein expression was analyzed by immunohistochemistry in 157 NSCLC samples. The relationship between PPM1D expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between PPM1D expression and prognosis of NSCLC patients. The relative mRNA expression of PPM1D was significantly elevated in NSCLC tissues as compared with adjacent noncancerous tissues (P < 0.001). The high expression of PPM1D in NSCLC tissues was significantly correlated with tumor grade (P = 0.006), tumor size (P = 0.017), clinical stage (P = 0.001), and lymph node metastases (P = 0.002). Kaplan-Meier survival analysis revealed that high PPM1D expression correlated with poor prognosis of NSCLC patients (P < 0.001). Multivariate analysis showed that PPM1D expression was an independent prognostic marker for overall survival of NSCLC patients. In conclusion, PPM1D plays an important role in the progression of NSCLC. PPM1D may potentially be used as an independent biomarker for the prognostic evaluation of NSCLC.