The epidermal growth factor receptor (EGFR) regulates many key biological processes including cell proliferation, survival and differentiation. It is frequently altered or amplified in cancers. Regulation of physiological EGFR function occurs at multiple levels, such as negative feedback regulation. We previously identified RAN-Binding Protein 6 (RanBP6), a protein of unknown functions, as a candidate EGFR interactor from an EGFR interactome study. Here, we validated that RanBP6, a member of the importin ? superfamily, interacts with EGFR and the proteins involved in nucleo-cytoplasmic transport. In addition, depletion of RanBP6 raised EGFR mRNA and protein levels, and upregulated EGFR promoter activity. Further studies revealed that RanBP6 represses EGFR transcription by modulating the subcellular localization of Signal transducer and activator of transcription 3 (STAT3). Focal deletions of the RANBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM). Silencing of RanBP6 promoted glioma growth in vivo and conferred resistance to EGFR tyrosine kinase inhibitors. Lastly, examination of RanBP6 substrates suggested RanBP6 is an importin for many tumor suppressors or oncoproteins. Our results demonstrated that RanBP6 functions as a novel EGFR feedback regulator to maintain EGFR homeostasis, and an importin for cancer-associated cargoes.