PR (PRDI-BF1 and RIZ) domain containing proteins (PRDM) have been indicated to play important roles in several human cancers. The objectives of this study were to determine the frequency and prognostic significance of PRDM1 and PRDM14 expression in a cohort of surgically resected non-small cell lung cancer (NSCLC) patients. Immunohistochemistry and Western blotting was used to detect the expression status of PRDM1 in primary tumors and PRDM14 for both primary lung cancers and matched lymph node metastases. Univariate and multivariate analysis were performed to determine the association between PRDM expression and prognosis. PRDM1 expression was observed in all NSCLC patients' tumor samples. PRDM14 was found to be increased expression in 35.65 % cases (46/129) for primary tumors and 39.68 % cases (25/63) for paired metastatic lymph nodes. Increased expression of PRDM14 correlated with differentiation of tumor cells significantly (P = 0.008). Western blotting analysis verified that PRDM14 associated with cell differentiation in NSCLC. The overall survival rates of patients with high PRDM14 expression and low PRDM14 expression were 41.30 and 65.06 %, respectively (hazard ratio: 3.051, 95 % CI: 1.752, 5.312, P < 0.0001). The progression-free survival rates were 34.78 % for patients in the high expression group and 59.03 % for patients in the low OLC1 expression group (hazard ratio: 2.775, 95 % CI: 1.648, 4.675, P < 0.0001). Thus, our study showed that increased expression of PRDM14 correlated with cell differentiation of NSCLC cells. PRDM14 was a potential biomarker for predicting unfavorable prognosis in NSCLC.