BACKGROUND/AIM: The aim of present study was to verify the effect of fluoxetine on DNA repair and metastatic potential in non-small cell lung cancer (NSCLC) in vitro. MATERIALS AND METHODS: Highly metastatic NSCLC CL1-5-F4 cells were used in this study. Cells were treated with different concentrations of fluoxetine or QNZ (NF-kB inhibitor) for 48 h. After treatment, cell viability, apoptotic signaling, NF-kB activation, expression of DNA repair and metastasis-associated proteins, and cell migration/invasion were evaluated by (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, flow cytometry, NF-kB reporter gene, western blotting, and cell migration/invasion assay, respectively. RESULTS: Fluoxetine induced apoptosis and reduced cell viability, NF-kB activation, expression of DNA repair and metastasis-associated proteins, and cell migration/invasion in CL1-5-F4 cells. Also, NF-kB activation was the critical factor in fluoxetine-inhibited metastatic potential. CONCLUSION: Fluoxetine induced apoptosis and inhibited DNA repair and metastatic potential in NSCLC CL1-5-F4 cells.