Type I interferons (IFNs) are potent inducers of antiviral and antiproliferative activities in vertebrates. IFNs cause activation of genes encoding antiviral proteins, such as p56 from the IFN-stimulated gene family. There are six tetratricopeptide repeat (TPR) motifs located at the N-terminal sequence of p56. Since TPR motifs are known to participate in protein-protein interactions, p56 may associate with various large protein complexes to modify their functions. Using a T7 phage display library, we identified ribosomal protein L15 (RPL15) as a novel interacting partner of p56. The p56-RPL15 interaction was confirmed by pull-down assays. Overexpression of p56 exhibited strong inhibition on the growth of RPL15-overexpressing cancer cells. Small interfering RNA targeting RPL15 not only reduced the growth rate of gastric cancer cells but also sensitized these cells to type I IFN-induced proliferative inhibition. Using site-directed mutagenesis, we also mapped the TPRs 1-4 of p56 as crucial domains to interact with RPL15. Taken together, our results demonstrated a novel interaction between p56 and RPL15. Differential regulation of p56 and RPL15 expression contributes to the antiproliferative capacity on gastric cancer cells, and further elucidation of their interaction may facilitate the development of new anticancer regimens.