c-Myc is a cellular onco-protein and a transcriptional activator important for cell growth, cell division, and tumorigenesis. Despite all that is known of its function, the mechanism of how c-Myc contributes to tumorigenesis is unclear. To gain insight into the mechanism through which c-Myc protein exerts its oncogenic activity, we performed large-scale, tandem repeat affinity purification and identified the F box only protein 8 (FBX8), an F-box- and Sec7 domain-containing protein, as a novel Myc-binding protein. The c-Myc/FBX8 interaction was mediated by the c-Myc box II (MBII) region. We also confirmed that Myc protein overexpression in 293T cells affected FBX8 cellular translocation and led to recovery from FBX8-mediated inhibition of ADP-ribosylation factor 6 (ARF6) function during cell invasion. Together, these results suggest that FBX8 is a novel c-Myc binding protein and that c-Myc induces cell invasive activity through the inhibition of FBX8 effects on ARF6 function during cell invasion.