Numerous genetic and epigenetic events driving tumorigenesis have been characterized. However, knowledge is lacking on the particular events required for the metastatic spread of cancer cells. The engulfment and cell motility 3 (ELMO3) gene plays an important role for the migratory potential of cells, but have not previously been studied in primary samples from cancer patients. We collected material from primary non-small cell lung cancer (NSCLC) tumors and paired brain or adrenal gland metastases from 26 patients and from 26 primary tumor samples from metastasis-free patients matched for age, gender, histology, T-stage, smoking status, and proportion of tumor cells. Using reverse transcriptase-quantitative PCR (RT-qPCR) ELMO3 was shown to be overexpressed in primary tumors from patients with distant metastases compared to normal lung tissue (p<0.001), and compared to primary tumors from metastasis-free patients (p<0.001). The increased expression coincided with decreased methylation levels of the ELMO3 promoter region. High expression and hypomethylation of ELMO3 were also observed when studying the paired brain and adrenal gland metastases. In conclusion, the putative oncogene, ELMO3, is overexpressed in NSCLC in combination with hypomethylation of its promoter and these cancer-specific events are associated with the formation of metastases.