Hepatoma-derived growth factor (HDGF) is a growth factor related to normal development and tumorigenesis; however, the mechanism of its mitogenic and angiogenic activity still remains unknown. Analysis of the HDGF interactome could be important for understanding its function and integrative mechanisms, because knowledge about HDGF interactors is very limited. In this study, through streptavidin-binding peptide (SBP) and Flag tag-based tandem affinity purification (SBP/Flag-TAP) coupled with LC-MS/MS, 106 proteins were shown to form complexes with HDGF. RNAs were also found in the HDGF complex through the SBP-tag based RNA co-immunoprecipitation (SBP-RIP) assay. Some of these interactions were confirmed by Co-IP and RT-PCR. We then found that the HATH domain was essential for HDGF interactions including protein-protein and protein-RNA interactions, and that in the absence of the HATH domain, NO-HATH could not form complex. The interactome suggests that HDGF is a multifunctional protein and participates in many cellular events, including ribosome biogenesis, RNA processing, DNA damage repair and transcriptional regulation. This new information about the HDGF interactome will further our understanding on HDGF-mediated cellular functions.