Objective: To detect the expression of CHCHD2 in non-small cell lung cancer (NSCLC) and normal tissues, and investigate its role and clinical significance on the process of NSCLC. Methods: The expression of CHCHD2 in NSCLC tissues and paired normal tissues of 209 cases was detected by immunohistochemistry method. The difference of CHCHD2 expression in clinicopathological parameters were analyzed by statistics. Results: Positive staining of CHCHD2 was mainly in cytoplasm. The positive expression rates of the CHCHD2 protein in NSCLC tissues was significantly higher than that in normal tissues (P<0.001). In SCCs, no significant difference was found that CHCHD2 expression among different subtypes (P=0.957). However, in ADCs there were significant difference of CHCHD2 expression in different subtypes (P=0.027). The expression of CHCHD2 was significant difference among groups of pathological grading groups of SSCs and ADCs (P=0.009, P=0.006). There were significant difference of the CHCHD2 expression among various groups of T and N clinical stages (P=0.011, P<0.001). Conclusion: CHCHD2 is over-expressed in NSCLC and differentially expressed proteins between NSCLC tissues and normal tissues. CHCHD2 over-expressed in NSCLC, might promote the development, invasion and metastasis of NSCLC, which is expected to be a prognostic indicator for NSCLC.