STRA13 is a hypoxia-inducible bHLH transcription factor implicated in the pVHL/HIF, TGF-beta, and Jak/STAT pathways. To further characterize the STRA13 protein-interacting network and mechanisms of STRA13-dependent transcription, we utilized yeast two-hybrid screening. Here we report on STRA13 interaction with the cell cycle-associated transcription factor MSP58. We demonstrated that the basic domain of STRA13 and the FHA domain of MSP58 are essential for this association. We performed phospho-peptide mapping of both MSP58 and STRA13 and showed that their association was modulated by the STRA13 phosphorylation status. STRA13/MSP58 complex formation protected both proteins from the proteasome-mediated degradation, extending their half-lives considerably. STRA13 and MSP58 synergistically co-operated in the STRA13 promoter-driven transcription repression. Both proteins were co-localized in the nucleus and showed transcript accumulation during the S phase of the cell cycle. Thus, we characterize a novel STRA13-associated transcription repression complex and provide a link between cell cycle regulation and STRA13 activity.